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Background: Recurrence of focal segmental glomerulosclerosis (FSGS) or steroid-resistant nephrotic syndrome (SRNS) after kidney transplant leads to significant morbidity and potentially earlier allograft loss. To date however, reported rates, risk factors and treatment outcomes have varied widely., Methods: We applied computational phenotypes to a multicenter aggregation of electronic health records data from 7 large pediatric health systems in the USA, to identify recurrence rates, risk factors, and treatment outcomes. We refined the data collection by chart review., Results: From > 7 million patients, we compared children with primary FSGS/SRNS who received a kidney transplant between 2009 and 2020 and who either developed recurrence (n = 67/165; 40.6%) or did not (n = 98/165). Serum albumin level at time of transplant was significantly lower and recipient HLA DR7 presence was significantly higher in the recurrence group. By 36 months post-transplant, complete remission occurred in 58.2% and partial remission in 17.9%. Through 6 years post-transplant, no remission after recurrence was associated with an increased risk of allograft loss over time (p < 0.0001), but any remission showed similar allograft survival and function decline to those with no recurrence. Since treatments were used in non-random fashion, using spline curves and multivariable non-linear analyses, complete + partial remission chance was significantly higher with greater plasmapheresis sessions, CTLA4-Ig doses or LDL-apheresis sessions. Only treatment with anti-CD20, CTLA4-Ig agents, or LDL-apheresis sessions were associated with complete remission. Excluding 25 patients with mutations did not significantly change our results., Conclusions: Our contemporary high-risk cohort had higher favorable response rates than most prior reports, from combinations of agents., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Purpose of Review: The impact of nephrolithiasis on skeletal growth and bone health across the life span of kidney stone formers is reviewed., Main Findings: Bone disease is an early event among kidney stone formers (SF), with distinct phenotypes according to each age, sex, menopausal status, dietary, hormonal and genetic factors. Nephrolithiasis-associated bone disorder is characterized by reduced bone mineral density (BMD) and histologically discloses low bone formation, high bone resorption and abnormal mineralization. Although hypercalciuria has been presumed to be pathogenic for bone loss in SF, the association of BMD with urinary calcium is not uniform in all studies. Hypocitraturia, metabolic disturbances, cytokines and receptors, growth factors and acid-base status may all influence skeletal outcomes. The potential link of bone disease with vascular calcification and cardiovascular disease among SF is discussed. The unique vulnerability of the younger skeleton to the effects of nephrolithiasis on attainment of peak bone mass and strength is highlighted and the association of bone loss with kidney stone formation early in life indicate the opportunity for intervention to reduce the risk of future bone fractures., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Cardiopulmonary bypass (CPB) is associated with hemolysis and acute kidney injury (AKI). The study aim was to determine if urine dipstick blood in infants after CPB was associated with AKI and urine neutrophil gelatinase-associated lipocalin (NGAL)., Methods: Infants who underwent CPB at a single center were enrolled prospectively between October 2017 and June 2019. Urine samples prior to CPB and 6 h after CPB cessation were analyzed in batch for NGAL and dipstick blood. AKI was defined using creatinine-based KDIGO criteria within 72 h of CPB. Spearman correlation examined associations between urine dipstick blood and NGAL at each time point. Linear regression estimated the associations between urine dipstick blood and log-transformed NGAL 6 h after CPB. Logistic regression estimated associations and compared discrimination between urine dipstick blood and NGAL for predicting AKI., Results: At baseline, 7/63 samples (11%) had > trace blood. Six hours after CPB, 62/98 samples (63%) had > trace blood and 26% had 3 + (large) blood. In total, 18/98 (18%) with a 6-h post-CPB sample had postoperative AKI. Urine dipstick blood values correlated with urine NGAL 6 h after CPB (r = 0.52, p < 0.01), but not at baseline (r = 0.06, p = 0.66). Those with 3 + (large) blood on urine dipstick had 6 times higher mean NGAL values compared to those with negative/trace blood (mean ratio 6.6, 95%CI 3.1-14.4, p < 0.01). Those with 3 + (large) blood had 8 times higher odds of AKI (OR 7.99, 95%CI 1.5-41.9, p = 0.01)., Conclusions: Urine dipstick blood post CPB may be a simple and inexpensive tool to help predict AKI in infants., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Aromatase inhibitors (AI) may improve height in short stature conditions; however, the effect in childhood cancer survivors (CCS) is unknown. We assessed final adult height (FAH) in CCS treated with AI and GH compared with those treated with GH alone., Methods: Retrospective cohort study of GH-deficient male CCS treated between 2007 and 2023. FAH was noted as the height at the fusion of growth plates or 18 years of age. Multivariable linear regression was used to examine treatment association with FAH, adjusting for other risk factors., Results: Ninety-two patients were included; 70 were treated with GH and 22 with combination AI/GH. The mean age at GH initiation did not differ between groups. The mean age at AI initiation was 13.7 ± 1.9 years. A greater proportion of patients in the AI/GH group were treated with stem cell transplantation, abdominal radiation, total body irradiation, and cis-retinoic acid (p < .01). Multivariable linear regression demonstrated no significant treatment association with FAH Z-score (β = 0.04, 95% CI: -0.9 to 0.9). History of spinal radiation (β = -0.93, 95% CI: -1.7 to -0.2), lower starting height Z-score (β = -0.8, 95% CI: -1.2 to -0.4), and greater difference between bone age and chronological age (β = -0.3, 95% CI: -0.5 to -0.07) were associated with lower FAH Z-score., Conclusions: Adjuvant AI was not associated with increased FAH in male CCS compared with GH monotherapy. Future work is needed to determine the optimal adjunctive treatment to maximize FAH for this population., (© 2024 Wiley Periodicals LLC.)

Study-specific data quality testing is an essential part of minimizing analytic errors, particularly for studies making secondary use of clinical data. We applied a systematic and reproducible approach for study-specific data quality testing to the analysis plan for PRESERVE, a 15-site, EHR-based observational study of chronic kidney disease in children. This approach integrated widely adopted data quality concepts with healthcare-specific evaluation methods. We implemented two rounds of data quality assessment. The first produced high-level evaluation using aggregate results from a distributed query, focused on cohort identification and main analytic requirements. The second focused on extended testing of row-level data centralized for analysis. We systematized reporting and cataloguing of data quality issues, providing institutional teams with prioritized issues for resolution. We tracked improvements and documented anomalous data for consideration during analyses. The checks we developed identified 115 and 157 data quality issues in the two rounds, involving completeness, data model conformance, cross-variable concordance, consistency, and plausibility, extending traditional data quality approaches to address more complex stratification and temporal patterns. Resolution efforts focused on higher priority issues, given finite study resources. In many cases, institutional teams were able to correct data extraction errors or obtain additional data, avoiding exclusion of 2 institutions entirely and resolving 123 other gaps. Other results identified complexities in measures of kidney function, bearing on the study's outcome definition. Where limitations such as these are intrinsic to clinical data, the study team must account for them in conducting analyses. This study rigorously evaluated fitness of data for intended use. The framework is reusable and built on a strong theoretical underpinning. Significant data quality issues that would have otherwise delayed analyses or made data unusable were addressed. This study highlights the need for teams combining subject-matter and informatics expertise to address data quality when working with real world data., Competing Interests: One author (MD) reports funding from Mallinckrodt, Inc. for development of the Glomerular Learning Network (GLEAN) for the study of kidney disease in children., (Copyright: © 2024 Razzaghi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

We investigated the risks of post-acute and chronic adverse kidney outcomes of SARS-CoV-2 infection in the pediatric population via a retrospective cohort study using data from the RECOVER program. We included 1,864,637 children and adolescents under 21 from 19 children's hospitals and health institutions in the US with at least six months of follow-up time between March 2020 and May 2023. We divided the patients into three strata: patients with pre-existing chronic kidney disease (CKD), patients with acute kidney injury (AKI) during the acute phase (within 28 days) of SARS-CoV-2 infection, and patients without pre-existing CKD or AKI. We defined a set of adverse kidney outcomes for each stratum and examined the outcomes within the post-acute and chronic phases after SARS-CoV-2 infection. In each stratum, compared with the non-infected group, patients with COVID-19 had a higher risk of adverse kidney outcomes. For patients without pre-existing CKD, there were increased risks of CKD stage 2+ (HR 1.20; 95% CI: 1.13-1.28) and CKD stage 3+ (HR 1.35; 95% CI: 1.15-1.59) during the post-acute phase (28 days to 365 days) after SARS-CoV-2 infection. Within the post-acute phase of SARS-CoV-2 infection, children and adolescents with pre-existing CKD and those who experienced AKI were at increased risk of progression to a composite outcome defined by at least 50% decline in estimated glomerular filtration rate (eGFR), eGFR <15 mL/min/1.73m 2 , End Stage Kidney Disease diagnosis, dialysis, or transplant., Competing Interests: Dr. Jhaveri is a consultant for AstraZeneca, Seqirus, Dynavax, receives an editorial stipend from Elsevier and Pediatric Infectious Diseases Society and royalties from Up To Date/Wolters Kluwer. Dr. Ruby Patel is the Primary Investigator for FIONA study, no stipend or compensation being given. Dr. Modi reports research funding outside of this work from the National Institutes of Health, Centers for Disease Control, the Patient-Centered Outcomes Research Institute, Travere Therapeutics, and Boehringer Ingelheim. He is also the current director of the Kidney Research Network Data Coordinating Center. Dr. Harshman reports research funding outside of this work from the National Institutes of Health. Dr. Harshman reports research funding outside of this work from Bayer Pharmaceuticals. Dr. Verghese reports research funding outside of this work from the Department of Defense and Viracor Pharmaceuticals. Dr. Dixon reports consultancies with Novartis Pharmaceuticals, Alexion Astra Zeneca Rare Disease, Apellis Pharmaceuticals, and Arrowhead Pharmaceuticals.

Background: There is interest in identifying novel filtration markers that lead to more accurate GFR estimates than current markers (creatinine and cystatin C) and are more consistent across demographic groups. We hypothesize that large-scale metabolomics can identify serum metabolites that are strongly influenced by glomerular filtration rate (GFR) and are more consistent across demographic variables than creatinine, which would be promising filtration markers for future investigation., Methods: We evaluated the consistency of associations between measured GFR (mGFR) and 887 common, known metabolites quantified by an untargeted chromatography- and spectroscopy-based metabolomics platform (Metabolon) performed on frozen blood samples from 580 participants in Chronic Kidney Disease in Children (CKiD), 674 participants in Modification of Diet in Renal Disease (MDRD) Study and 962 participants in African American Study of Kidney Disease and Hypertension (AASK). We evaluated metabolite-mGFR correlation association with metabolite class, molecular weight, assay platform and measurement coefficient of variation (CV). Among metabolites with strong negative correlations with mGFR ( r < -0.5), we assessed additional variation by age (height in children), sex, race and body mass index (BMI)., Results: A total of 561 metabolites (63%) were negatively correlated with mGFR. Correlations with mGFR were highly consistent across study, sex, race and BMI categories (correlation of metabolite-mGFR correlations between 0.88 and 0.95). Amino acids, carbohydrates and nucleotides were more often negatively correlated with mGFR compared with lipids, but there was no association with metabolite molecular weight, liquid chromatography/mass spectrometry platform and measurement CV. Among 114 metabolites with strong negative associations with mGFR ( r < -0.5), 27 were consistently not associated with age (height in children), sex or race., Conclusions: The majority of metabolite-mGFR correlations were negative and consistent across sex, race, BMI and study. Metabolites with consistent strong negative correlations with mGFR and non-association with demographic variables may represent candidate markers to improve estimation of GFR., Competing Interests: The authors declare no conflict of interest relevant to the data presented in this manuscript., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background: Children with CKD are at risk for impaired neurocognitive functioning. We investigated metabolomic associations with neurocognition in children with CKD., Methods: We leveraged data from the Chronic Kidney Disease in Children (CKiD) study and the Neurocognitive Assessment and Magnetic Resonance Imaging Analysis of Children and Young Adults with Chronic Kidney Disease (NiCK) study. CKiD is a multi-institutional cohort that enrolled children aged 6 months to 16 years with eGFR 30-90 ml/min per 1.73 m 2 ( n =569). NiCK is a single-center cross-sectional study of participants aged 8-25 years with eGFR<90 ml/min per 1.73 m 2 ( n =60) and matched healthy controls ( n =67). Untargeted metabolomic quantification was performed on plasma (CKiD, 622 metabolites) and serum (NiCK, 825 metabolites) samples. Four neurocognitive domains were assessed: intelligence, attention regulation, working memory, and parent ratings of executive function. Repeat assessments were performed in CKiD at 2-year intervals. Linear regression and linear mixed-effects regression analyses adjusting for age, sex, delivery history, hypertension, proteinuria, CKD duration, and glomerular versus nonglomerular diagnosis were used to identify metabolites associated with neurocognitive z-scores. Analyses were performed with and without adjustment for eGFR., Results: There were multiple metabolite associations with neurocognition observed in at least two of the analytic samples (CKiD baseline, CKiD follow-up, and NiCK CKD). Most of these metabolites were significantly elevated in children with CKD compared with healthy controls in NiCK. Notable signals included associations with parental ratings of executive function: phenylacetylglutamine, indoleacetylglutamine, and trimethylamine N-oxide-and with intelligence: γ -glutamyl amino acids and aconitate., Conclusions: Several metabolites were associated with neurocognitive dysfunction in pediatric CKD, implicating gut microbiome-derived substances, mitochondrial dysfunction, and altered energy metabolism, circulating toxins, and redox homeostasis., Podcast: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/CJASN/2023&#95;11&#95;17&#95;CJN0000000000000318.mp3., (Copyright © 2023 by the American Society of Nephrology.)

Introduction: Fibroblast growth factor 23 (FGF23) has direct effects on the vasculature and myocardium, and high levels of FGF23 are a risk factor for cardiovascular disease (CVD); however, the impact of FGF23 on CVD in primary proteinuric glomerulopathies has not been addressed., Methods: The associations of baseline plasma intact FGF23 levels with resting blood pressure (BP) and lipids over time among adults and children with proteinuric glomerulopathies enrolled in the Nephrotic Syndrome Study Network (NEPTUNE) were analyzed using generalized estimating equation regression analyses. Models were adjusted for age, sex, glomerular diagnosis, follow-up time, estimated glomerular filtration rate, urine protein/creatinine ratio, obesity, and serum phosphorous levels., Results: Two hundred and four adults with median FGF23 77.5 (IQR 51.3-119.3) pg/mL and 93 children with median FGF23 62.3 (IQR 44.6-83.6) pg/mL were followed for a median of 42 (IQR 20.5-54) months. In adjusted models, each 1 µg/mL increase in FGF23 was associated with a 0.3 increase in systolic BP index at follow-up (p &lt; 0.001). Greater baseline FGF23 was associated with greater odds of hypertensive BP (OR = 1.0003; 95% CI 1.001-1.006, p = 0.03) over time. Compared to tertile 1, tertile 2 (OR = 2.1; 95% CI 1.12-3.99, p = 0.02), and tertile 3 (OR = 3; 95% CI 1.08-8.08, p = 0.04), FGF23 levels were associated with greater odds of hypertensive BP over time. Tertile 2 was associated with greater triglycerides compared to tertile 1 (OR = 48.1; 95% CI 4.4-91.9, p = 0.03)., Conclusion: Overall, higher baseline FGF23 was significantly associated with hypertensive BP over time in individuals with proteinuric glomerulopathies. Further study of FGF23 as a therapeutic target for reducing CVD in proteinuric glomerular disease is warranted., (© 2023 S. Karger AG, Basel.)

Background: Identification of abnormal blood pressure (BP) in children requires normative data. We sought to examine the feasibility of using "real-world" office BP data obtained from electronic health records (EHR) to generate age-, sex- and height-specific BP percentiles for children., Methods: Using data collected 01/01/2009-8/31/2021 from eight large children's healthcare organisations in PEDSnet, we applied a mixed-effects polynomial regression model with random slopes to generate Z-scores and BP percentiles and compared them with currently used normative BP distributions published in the 2017 American Academy of Paediatrics (AAP) Clinical Practise Guidelines (CPG)., Findings: We identified a study sample of 292,412 children (1,085,083 BP measurements), ages 3-17 years (53% female), with no chronic medical conditions, who were not overweight/obese and who were primarily seen for general paediatric care in outpatient settings. Approximately 45,000-75,000 children contributed data to each age category. The PEDSnet systolic BP percentile values were 1-4 mmHg higher than AAP CPG BP values across age-sex-height groups, with larger differences observed in younger children. Diastolic BP values were also higher in younger children; starting with age 7 years, diastolic BP percentile values were 1-3 mmHg lower than AAP CPG values. Cohen's Kappa was 0.90 for systolic BP, 0.66 for diastolic BP, and 0.80 overall indicating excellent agreement between PEDSnet and 2017 AAP CPG data for systolic BP and substantial agreement for diastolic BP., Interpretation: Our analysis indicates that real-word EHR data can be used to generate BP percentiles consistent with current clinical practise on BP management in children., Funding: Funding for this work was provided by the Preserving Kidney Function in Children with Chronic Kidney Disease (PRESERVE) study; Patient-Centred Outcomes Research Institute (PCORI) RD-2020C2020338 (Principal Investigator: Dr. Forrest; Co-Principal Investigator: Dr. Denburg)., Competing Interests: Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Influenza infections contribute to excess healthcare utilization, morbidity, and mortality in individuals with glomerular disease (GD); however, influenza vaccination may not yield protective immune responses in this high-risk patient population. The objective of the present study was to describe influenza vaccine administration from 2010 to 2019 and explore the effectiveness of influenza vaccination in patients with GD., Methods: We conducted an observational cohort study using healthcare claims for seasonal influenza vaccination (exposure) as well as influenza and influenza-like illness (outcomes) from commercially insured children and adults <65 years of age with primary GD in the Merative MarketScan Research Databases. Propensity score-weighted cox proportional hazards models and ratio-of-hazard ratios (RHR) analyses were used to compare influenza infection risk in years where seasonal influenza vaccines matched or mismatched circulating viral strains., Results: The mean proportion of individuals vaccinated per season was 23% (range 19%-24%). In pooled analyses comparing matched to mismatched seasons, vaccination was minimally protective for both influenza (RHR 0.86, 95% confidence interval [CI]: 0.52-1.41) and influenza-like illness (RHR 0.86, 95% CI 0.59-1.24), though estimates were limited by sample size., Conclusion: Rates of influenza vaccination are suboptimal among patients with GD. Protection from influenza after vaccination may be poor, leading to excess infection-related morbidity in this vulnerable population., (© 2023 International Society of Nephrology. Published by Elsevier Inc.)

Rationale & Objective: PRESERVE seeks to provide new knowledge to inform shared decision-making regarding blood pressure (BP) management for pediatric chronic kidney disease (CKD). PRESERVE will compare the effectiveness of alternative strategies for monitoring and treating hypertension on preserving kidney function; expand the National Patient-Centered Clinical Research Network (PCORnet) common data model by adding pediatric- and kidney-specific variables and linking electronic health record data to other kidney disease databases; and assess the lived experiences of patients related to BP management., Study Design: Multicenter retrospective cohort study (clinical outcomes) and cross-sectional study (patient-reported outcomes [PROs])., Setting & Participants: PRESERVE will include approximately 20,000 children between January 2009-December 2022 with mild-moderate CKD from 15 health care institutions that participate in 6 PCORnet Clinical Research Networks (PEDSnet, STAR, GPC, PaTH, CAPRiCORN, and OneFlorida+). The inclusion criteria were ≥1 nephrologist visit and ≥2 estimated glomerular filtration rate (eGFR) values in the range of 30 to <90 mL/min/1.73 m 2 separated by ≥90 days without an intervening value ≥90 mL/min/1.73 m 2 and no prior dialysis or kidney transplant., Exposures: BP measurements (clinic-based and 24-hour ambulatory BP); urine protein; and antihypertensive treatment by therapeutic class., Outcomes: The primary outcome is a composite event of a 50% reduction in eGFR, eGFR of <15 mL/min/1.73 m 2 , long-term dialysis or kidney transplant. Secondary outcomes include change in eGFR, adverse events, and PROs., Analytical Approach: Longitudinal models for dichotomous (proportional hazards or accelerated failure time) and continuous (generalized linear mixed models) clinical outcomes; multivariable linear regression for PROs. We will evaluate heterogeneity of treatment effect by CKD etiology and degree of proteinuria and will examine variation in hypertension management and outcomes based on socio-demographics., Limitations: Causal inference limited by observational analyses., Conclusions: PRESERVE will leverage the PCORnet infrastructure to conduct large-scale observational studies that address BP management knowledge gaps for pediatric CKD, focusing on outcomes that are meaningful to patients., Plain-Language Summary: Hypertension is a major modifiable contributor to loss of kidney function in chronic kidney disease (CKD). The purpose of PRESERVE is to provide evidence to inform shared decision-making regarding blood pressure management for children with CKD. PRESERVE is a consortium of 16 health care institutions in PCORnet, the National Patient-Centered Clinical Research Network, and includes electronic health record data for >19,000 children with CKD. PRESERVE will (1) expand the PCORnet infrastructure for research in pediatric CKD by adding kidney-specific variables and linking electronic health record data to other kidney disease databases; (2) compare the effectiveness of alternative strategies for monitoring and treating hypertension on preserving kidney function; and (3) assess the lived experiences of patients and caregivers related to blood pressure management., (© 2023 Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc.)

Development of clinical guidelines and recommendations to address the care of pediatric patients with chronic kidney disease (CKD) has rarely included the perspectives of providers from a variety of health care disciplines or the patients and parents themselves. Accordingly, the National Kidney Foundation hosted an in-person, one and a half-day workshop that convened a multidisciplinary group of physicians, allied health care professionals, and pediatric patients with CKD and their parents, with the goal of developing key clinical recommendations regarding best practices for the clinical management of pediatric patients living with CKD. The key clinical recommendations pertained to 5 broad topics: addressing the needs of patients and parents/caregivers; modifying the progression of CKD; clinical management of CKD-mineral and bone disorder and growth retardation; clinical management of anemia, cardiovascular disease, and hypertension; and transition and transfer of pediatric patients to adult nephrology care. This report describes the recommendations generated by the participants who attended the workshop., (Copyright © 2022 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Vitamin D deficiency is common in glomerular disease. Supplementation may be ineffective due to ongoing urinary losses of vitamin D binding protein. We sought to determine if daily cholecalciferol supplementation would increase vitamin D concentrations in children with glomerular disease and persistent proteinuria, without adverse effects., Methods: Eighteen participants at least 5 years of age with primary glomerular disease and urine protein:creatinine ratio ≥ 0.5 were enrolled from four pediatric nephrology practices to receive cholecalciferol supplementation: 4,000 IU or 2,000 IU per day for serum 25 hydroxyvitamin vitamin D (25OHD) concentrations < 20 ng/mL and 20 ng/mL to < 30 ng/mL, respectively. Measures of vitamin D and mineral metabolism were obtained at baseline and weeks 6 and 12. Multivariable generalized estimating equation (GEE) regression estimated mean percent changes in serum 25OHD concentration., Results: Median baseline 25OHD was 12.8 ng/mL (IQR 9.3, 18.9) and increased to 27.8 ng/mL (20.5, 36.0) at week 6 (p < 0.001) without further significant increase at week 12. A total of 31% of participants had a level ≥ 30 ng/mL at week 12. Supplementation was stopped in two participants at week 6 for mildly elevated calcium and phosphorus, respectively, with subsequent declines in 25OHD of > 20 ng/mL. In the adjusted GEE model, 25OHD was 102% (95% CI: 64, 141) and 96% (95% CI: 51, 140) higher versus baseline at weeks 6 and 12, respectively (p < 0.001)., Conclusion: Cholecalciferol supplementation in vitamin D deficient children with glomerular disease and persistent proteinuria safely increases 25OHD concentration. Ideal dosing to fully replete 25OHD concentrations in this population remains unknown., Clinical Trial: NCT01835639. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2022. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Background: The objectives of this study were to use electronic health record data from a US national multicenter pediatric network to identify a large cohort of children with CKD, evaluate CKD progression, and examine clinical risk factors for kidney function decline., Methods: This retrospective cohort study identified children seen between January 1, 2009, to February 28, 2022. Data were from six pediatric health systems in PEDSnet. We identified children aged 18 months to 18 years who met criteria for CKD: two eGFR values <90 and ≥15 ml/min per 1.73 m2 separated by ≥90 days without an intervening value ≥90. CKD progression was defined as a composite outcome: eGFR <15 ml/min per 1.73 m2, ≥50% eGFR decline, long-term dialysis, or kidney transplant. Subcohorts were defined based on CKD etiology: glomerular, nonglomerular, or malignancy. We assessed the association of hypertension (≥2 visits with hypertension diagnosis code) and proteinuria (≥1 urinalysis with ≥1+ protein) within 2 years of cohort entrance on the composite outcome., Results: Among 7,148,875 children, we identified 11,240 (15.7 per 10,000) with CKD (median age 11 years, 50% female). The median follow-up was 5.1 (interquartile range 2.8-8.3) years, the median initial eGFR was 75.3 (interquartile range 61-83) ml/min per 1.73 m2, 37% had proteinuria, and 35% had hypertension. The following were associated with CKD progression: lower eGFR category (adjusted hazard ratio [aHR] 1.44 [95% confidence interval (95% CI), 1.23 to 1.69], aHR 2.38 [95% CI, 2.02 to 2.79], aHR 5.75 [95% CI, 5.05 to 6.55] for eGFR 45-59 ml/min per 1.73 m2, 30-44 ml/min per 1.73 m2, 15-29 ml/min per 1.73 m2 at cohort entrance, respectively, when compared with eGFR 60-89 ml/min per 1.73 m2), glomerular disease (aHR 2.01 [95% CI, 1.78 to 2.28]), malignancy (aHR 1.79 [95% CI, 1.52 to 2.11]), proteinuria (aHR 2.23 [95% CI, 1.89 to 2.62]), hypertension (aHR 1.49 [95% CI, 1.22 to 1.82]), proteinuria and hypertension together (aHR 3.98 [95% CI, 3.40 to 4.68]), count of complex chronic comorbidities (aHR 1.07 [95% CI, 1.05 to 1.10] per additional comorbid body system), male sex (aHR 1.16 [95% CI, 1.05 to 1.28]), and younger age at cohort entrance (aHR 0.95 [95% CI, 0.94 to 0.96] per year older)., Conclusions: In large-scale real-world data for children with CKD, disease etiology, albuminuria, hypertension, age, male sex, lower eGFR, and greater medical complexity at start of follow-up were associated with more rapid decline in kidney function., (Copyright © 2023 by the American Society of Nephrology.)

Background: Fluid overload is associated with morbidity and mortality in children receiving dialysis. Accurate clinical assessment is difficult, and using deuterium oxide (D 2 O) to measure total body water (TBW) is impractical. We investigated the use of ultrasound (US), bioimpedance spectroscopy (BIS), and anthropometry to assess fluid removal in children receiving maintenance hemodialysis (HD)., Methods: Participants completed US, BIS, and anthropometry immediately before and 1-2 h after HD for up to five sessions. US measured inferior vena cava (IVC) diameter, lung B-lines, muscle elastography, and dermal thickness. BIS measured the volume of extracellular (ECF) and intracellular (ICF) fluid. Anthropometry included mid-upper arm, calf and ankle circumferences, and triceps skinfold thickness. D 2 O was performed once pre-HD. We assessed the change in study measures pre- versus post-HD, and the correlation of change in study measures with percent change in body weight (%∆BW). We also assessed the agreement between TBW measured by BIS and D 2 O., Results: Eight participants aged 3.4-18.5 years were enrolled. Comparison of pre- and post-HD measures showed significant decrease in IVC diameters, lung B-lines, dermal thickness, BIS %ECF, mid-upper arm circumference, ankle, and calf circumference. Repeated measures correlation showed significant relationships between %∆BW and changes in BIS ECF (r rm =0.51, 95% CI 0.04, 0.80) and calf circumference (r rm =0.80, 95% CI 0.51, 0.92). BIS TBW correlated with D 2 O TBW but overestimated TBW by 2.2 L (95% LOA, -4.75 to 0.42)., Conclusion: BIS and calf circumference may be helpful to assess changes in fluid status in children receiving maintenance HD. IVC diameter, lung B-lines and dermal thickness are potential candidates for future studies., (© 2023. The Author(s).)

Background: Children with glomerular disease have unique risk factors for compromised bone health. Studies addressing skeletal complications in this population are lacking., Methods: This retrospective cohort study utilized data from PEDSnet, a national network of pediatric health systems with standardized electronic health record data for more than 6.5 million patients from 2009 to 2021. Incidence rates (per 10,000 person-years) of fracture, slipped capital femoral epiphysis (SCFE), and avascular necrosis/osteonecrosis (AVN) in 4598 children and young adults with glomerular disease were compared with those among 553,624 general pediatric patients using Poisson regression analysis. The glomerular disease cohort was identified using a published computable phenotype. Inclusion criteria for the general pediatric cohort were two or more primary care visits 1 year or more apart between 1 and 21 years of age, one visit or more every 18 months if followed >3 years, and no chronic progressive conditions defined by the Pediatric Medical Complexity Algorithm. Fracture, SCFE, and AVN were identified using SNOMED-CT diagnosis codes; fracture required an associated x-ray or splinting/casting procedure within 48 hours., Results: We found a higher risk of fracture for the glomerular disease cohort compared with the general pediatric cohort in girls only (incidence rate ratio [IRR], 1.6; 95% CI, 1.3 to 1.9). Hip/femur and vertebral fracture risk were increased in the glomerular disease cohort: adjusted IRR was 2.2 (95% CI, 1.3 to 3.7) and 5 (95% CI, 3.2 to 7.6), respectively. For SCFE, the adjusted IRR was 3.4 (95% CI, 1.9 to 5.9). For AVN, the adjusted IRR was 56.2 (95% CI, 40.7 to 77.5)., Conclusions: Children and young adults with glomerular disease have significantly higher burden of skeletal complications than the general pediatric population., (Copyright © 2022 by the American Society of Nephrology.)

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)., (© 2022. The Author(s).)

BACKGROUNDMetabolomic profiling in individuals with chronic kidney disease (CKD) has the potential to identify novel biomarkers and provide insight into disease pathogenesis.METHODSWe examined the association between blood metabolites and CKD progression, defined as the subsequent development of end-stage renal disease (ESRD) or estimated glomerular filtrate rate (eGFR) halving, in 1,773 participants of the Chronic Renal Insufficiency Cohort (CRIC) study, 962 participants of the African-American Study of Kidney Disease and Hypertension (AASK), and 5,305 participants of the Atherosclerosis Risk in Communities (ARIC) study.RESULTSIn CRIC, more than half of the measured metabolites were associated with CKD progression in minimally adjusted Cox proportional hazards models, but the number and strength of associations were markedly attenuated by serial adjustment for covariates, particularly eGFR. Ten metabolites were significantly associated with CKD progression in fully adjusted models in CRIC; 3 of these metabolites were also significant in fully adjusted models in AASK and ARIC, highlighting potential markers of glomerular filtration (pseudouridine), histamine metabolism (methylimidazoleacetate), and azotemia (homocitrulline). Our findings also highlight N-acetylserine as a potential marker of kidney tubular function, with significant associations with CKD progression observed in CRIC and ARIC.CONCLUSIONOur findings demonstrate the application of metabolomics to identify potential biomarkers and causal pathways in CKD progression.FUNDINGThis study was supported by the NIH (U01 DK106981, U01 DK106982, U01 DK085689, R01 DK108803, and R01 DK124399).

Rationale & Objective: Infections cause morbidity and mortality in patients with glomerular disease. The relative contributions from immunosuppression exposure and glomerular disease activity to infection risk are not well characterized. To address this unmet need, we characterized the relationship between time-varying combinations of immunosuppressant exposure and infection-related acute care events while controlling for disease activity, among individuals with glomerular disease., Study Design: Prospective, multicenter, observational cohort study., Setting & Participants: Adults and children with biopsy-proven minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or immunoglobulin A nephropathy/vasculitis were enrolled at 71 clinical sites in North America and Europe. A total of 2,388 Cure Glomerulonephropathy Network participants (36% aged <18 years) had at least 1 follow-up visit and were included in the analysis., Exposures: Immunosuppression exposure modeled on a weekly basis., Outcome: Infections leading to an emergency department visit or hospitalization., Analytical Approach: Marginal structural models were used to estimate the effect of time-varying immunosuppression exposure on hazard of first infection-related acute care event while accounting for baseline sociodemographic and clinical factors, and time-varying disease activity., Results: A total of 2,388 participants were followed for a median of 3.2 years (interquartile range, 1.6-4.6), and 15% experienced at least 1 infection-related emergency department visit or hospitalization. Compared to no immunosuppression exposure, steroid exposure, steroid with any other immunosuppressant, and nonsteroid immunosuppressant exposure were associated with a 2.65-fold (95% CI, 1.83-3.86), 2.68-fold (95% CI, 1.95-3.68), and 1.7-fold (95% CI, 1.29-2.24) higher risk of first infection, respectively., Limitations: Absence of medication dosing data, lack of a control group, and potential bias in ascertainment of outcome events secondary to the coronavirus 2 pandemic., Conclusions: Corticosteroids with or without concomitant additional immunosuppression significantly increased risk of infection leading to acute care utilization in adults and children with glomerular disease., (© 2022 The Authors.)

Introduction: The American Academy of Pediatrics recommends blood pressure screening at every health care encounter in children younger than 3 years if they have a history of prematurity or other neonatal complications requiring intensive care because these children have an increased risk for hypertension., Methods: A multidisciplinary team conducted a quality improvement initiative to improve blood pressure screening at a single-center outpatient neonatal follow-up clinic. We developed a focused intervention program including a standardized blood pressure measurement protocol, staff training and education, and streamlined documentation. We conducted two Plan-Do-Study-Act cycles from November 2019 to January 2021. The outcome measure was the percentage of patients with a blood pressure measurement. Process measures included the percentage of medical assistants educated on the new protocol, percentage of patients 3 years, and younger old with the first blood pressure measurement taken from the right arm, and the percentage of patients 1 year and younger with 3 documented blood pressures. The balancing measure was staff satisfaction with time to obtain vital signs. We used statistical process control charts and Wilcoxon rank-sum test., Results: At baseline, only 15.3% of patients had documented blood pressure. During the 10-month intervention period, there were 954 patient visits. Overall, blood pressure measurement increased to 54.7% with study interventions. The balancing measure was not negatively impacted., Conclusions: After implementing a program of focused interventions, we substantially improved the frequency of blood pressure measurements and increased adherence to American Academy of Pediatrics screening guidelines. Improved blood pressure screening allows us to identify and evaluate at-risk infants after hospital discharge., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Untargeted plasma metabolomic profiling combined with machine learning (ML) may lead to discovery of metabolic profiles that inform our understanding of pediatric CKD causes. We sought to identify metabolomic signatures in pediatric CKD based on diagnosis: FSGS, obstructive uropathy (OU), aplasia/dysplasia/hypoplasia (A/D/H), and reflux nephropathy (RN)., Methods: Untargeted metabolomic quantification (GC-MS/LC-MS, Metabolon) was performed on plasma from 702 Chronic Kidney Disease in Children study participants ( n : FSGS=63, OU=122, A/D/H=109, and RN=86). Lasso regression was used for feature selection, adjusting for clinical covariates. Four methods were then applied to stratify significance: logistic regression, support vector machine, random forest, and extreme gradient boosting. ML training was performed on 80% total cohort subsets and validated on 20% holdout subsets. Important features were selected based on being significant in at least two of the four modeling approaches. We additionally performed pathway enrichment analysis to identify metabolic subpathways associated with CKD cause., Results: ML models were evaluated on holdout subsets with receiver-operator and precision-recall area-under-the-curve, F1 score, and Matthews correlation coefficient. ML models outperformed no-skill prediction. Metabolomic profiles were identified based on cause. FSGS was associated with the sphingomyelin-ceramide axis. FSGS was also associated with individual plasmalogen metabolites and the subpathway. OU was associated with gut microbiome-derived histidine metabolites., Conclusion: ML models identified metabolomic signatures based on CKD cause. Using ML techniques in conjunction with traditional biostatistics, we demonstrated that sphingomyelin-ceramide and plasmalogen dysmetabolism are associated with FSGS and that gut microbiome-derived histidine metabolites are associated with OU., (Copyright © 2022 by the American Society of Nephrology.)

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., (Copyright © 2022 by the American Society of Nephrology.)

Background: Primary nephrotic syndromes are rare diseases which can impede adequate sample size for observational patient-oriented research and clinical trial enrollment. A computable phenotype may be powerful in identifying patients with these diseases for research across multiple institutions., Methods: A comprehensive algorithm of inclusion and exclusion ICD-9 and ICD-10 codes to identify patients with primary nephrotic syndrome was developed. The algorithm was executed against the PCORnet CDM at three institutions from January 1, 2009 to January 1, 2018, where a random selection of 50 cases and 50 noncases (individuals not meeting case criteria seen within the same calendar year and within 5 years of age of a case) were reviewed by a nephrologist, for a total of 150 cases and 150 noncases reviewed. The classification accuracy (sensitivity, specificity, positive and negative predictive value, F1 score) of the computable phenotype was determined., Results: The algorithm identified a total of 2708 patients with nephrotic syndrome from 4,305,092 distinct patients in the CDM at all sites from 2009 to 2018. For all sites, the sensitivity, specificity, and area under the curve of the algorithm were 99% (95% CI, 97% to 99%), 79% (95% CI, 74% to 85%), and 0.9 (0.84 to 0.97), respectively. The most common causes of false positive classification were secondary FSGS (nine out of 39) and lupus nephritis (nine out of 39)., Conclusion: This computable phenotype had good classification in identifying both children and adults with primary nephrotic syndrome utilizing only ICD-9 and ICD-10 codes, which are available across institutions in the United States. This may facilitate future screening and enrollment for research studies and enable comparative effectiveness research. Further refinements to the algorithm including use of laboratory data or addition of natural language processing may help better distinguish primary and secondary causes of nephrotic syndrome., Competing Interests: C. Tran reports being a scientific advisor or member of Frontiers in Pediatrics Review Editor on the Editorial Board of Pediatric Nephrology. D. Gipson reports having consultancy agreements, through the University of Michigan, with AstraZeneca, Boehringer Ingelheim, Roche/Genentech, and Vertex Pharmaceuticals; reports receiving research funding, through the University of Michigan, from Atrium Health Medical Foundation, Boehringer Ingelheim, Centers for Disease Control, Food and Drug Administration, Goldfinch Bio, National Institutes of Health, Novartis, Reata, and Travere; and reports being a scientific advisor or member of the American Society of Pediatric Nephrology, American Society of Nephrology, and International Society of Pediatric Nephrology. H. Desmond reports receiving research funding through a percentage of salary from the University of Michigan, funded by Boehringer Ingelheim. I. Ayoub reports receiving honoraria from the American College of Rheumatology; reports being a scientific advisor or member of the Journal of Clinical Nephrology (Editorial Board) and the Lupus Foundation of America (advisory board). L. Mariani reports having consultancy agreements with, and receiving honoraria from, Calliditas Therapeutics Advisory Board, CKD Advisory Committee, Reata Pharmaceuticals, and Travere Therapeutics Advisory Board; reports receiving research funding from Boehringer Ingelheim; reports receiving honoraria from American Society of Nephrology Board Review Course and Update; and reports being a scientific advisor or member of Calliditas Therapeutics, Reata Pharmaceuticals, and Travere Therapeutics. M. Denburg reports having consultancy agreements with Trisalus Life Sciences (spouse); reports having an ownership interest in In-Bore LLC (spouse) and Precision Guided Interventions LLC (spouse); reports receiving research funding from Mallinckrodt; reports being a scientific advisor or member of NKF Delaware Valley Medical Advisory Board and Trisalus Life Sciences Scientific Advisory Board (spouse); and reports other interests/relationships with the American Society of Pediatric Nephrology Research and Program Committees and the National Kidney Foundation Pediatric Education Planning Committee. M. Matheny reports consultancy agreements with National Institutes of Health- Veterans Affairs- Department of Defense Pain Management Grant Consortium (PMC3); reports being a scientific advisor or member of Scientific Merit Review Board Study Section, VA Health Services Research and Development (HSR&D), Informatics and Methods Section, the Steering Committee of Indianapolis VA HSR&D Center of Innovation; and the Steering Committee of VA HSR&D VA Information Resource Center. S. Almaani reports having consultancy agreements with Aurinia Pharmaceuticals and Kezar Life Sciences; reports receiving research funding from Gilead Sciences; reports being a scientific advisor or member Clinical Nephrology Editorial Board; and reports speakers bureau from Aurinia Pharmaceuticals. S. Massengill reports having consultancy agreements with Guidepoint Group; reports being a scientific advisor or member of the Editorial Board of online Glomerular Disease Journal (Karger Publishers). All remaining authors have nothing to disclose., (Copyright © 2021 by the American Society of Nephrology.)

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 m 2 ; 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 m 2 , 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 <60 ml/min per 1.73 m 2 , a higher level of tetrahydrocortisol sulfate was associated with lower risk of progression (hazard ratio, 0.8; 95% confidence interval, 0.7 to 0.9)., 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., (Copyright © 2021 by the American Society of Nephrology.)

Objectives: Inflammatory bowel disease (IBD) is associated with increased risk of venous thromboembolism (VTE). Despite this recognized risk, there are limited data and no anticoagulation guidelines for hospitalized pediatric IBD patients. The objectives of this study were to characterize pediatric IBD patients with VTE and determine risk factors., Methods: This was a nested case-control study comparing hospitalized children with IBD diagnosed with VTE to those without VTE over a decade at a large referral center. Standard descriptive statistics were used to describe the VTE group. Multivariable conditional logistic regression was used to assess risk factors., Results: Twenty-three cases were identified. Central venous catheter (CVC) presence (odds ratio [OR] 77.9; 95% confidence interval [CI]: 6.9--880.6; P < 0.001) and steroid use (OR 12.7; 95% CI: 1.3--126.4; P = 0.012) were independent risk factors. Median age at VTE was 17 years (interquartile range [IQR] 13.5--18.2), and in 48%, VTE was the indication for admission. Median duration of anticoagulation was 3.8 months (IQR 2.3--7.6), and there were no major bleeding events for patients on anticoagulation. There were no patients with known sequelae from VTE, though 22% had severe VTE that required interventions., Conclusions: Pediatric patients with IBD are at risk for VTE, although the absolute risk remains relatively low. The safety and efficacy of pharmacologic thromboprophylaxis needs to be further evaluated in this population with attention to risk factors, such as steroid use and presence of CVC., Competing Interests: The authors report no conflict of interests., (Copyright © 2021 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Objective: To assess the prevalence of therapy-related kidney outcomes in survivors of Wilms tumor (WT)., Study Design: This prospective cohort study included survivors of WT who were ≥5 years old and ≥1 year from completing therapy, excluding those with preexisting hypertension, prior dialysis, or kidney transplant. Participants completed 24-hour ambulatory blood pressure monitoring (ABPM). Abnormal blood pressure (BP) was defined as ≥90th percentile. Masked hypertension was defined as having normal office BP and abnormal ABPM findings. Urine was analyzed for kidney injury molecule-1, interleukin-18, epidermal growth factor, albumin, and creatinine. The estimated glomerular filtration rate (eGFR) was calculated using the bedside chronic kidney disease in children equation. Recent kidney ultrasound examinations and echocardiograms were reviewed for contralateral kidney size and left ventricular hypertrophy, respectively. Clinical follow-up data were collected for approximately 2 years after study enrollment., Results: Thirty-two participants (median age, 13.6 years [IQR, 10.5-16.3 years]; 75% stage 3 or higher WT) were evaluated at a median of 8.7 years (IQR, 6.5-10.8 years) after therapy; 29 participants underwent unilateral radical nephrectomy, 2 bilateral partial nephrectomy, and 1 radical and contralateral partial nephrectomy. In this cohort, 72% received kidney radiotherapy and 75% received doxorubicin. Recent median eGFR was 95.6 mL/min/1.73 m 2 (IQR, 84.6-114.0; 11 [34%] had an eGFR of <90 mL/min/1.73 m 2 ). Abnormal ABPM results were found in 22 of 29 participants (76%), masked hypertension in 10 of 29 (34%), and microalbuminuria in 2 of 32 (6%). Of the 32 participants, 22 (69%) had abnormal epidermal growth factor; few had abnormal kidney injury molecule-1 or interleukin-18. Seven participants with previous unilateral nephrectomy lacked compensatory contralateral kidney hypertrophy. None had left ventricular hypertrophy., Conclusions: In survivors of WT, adverse kidney outcomes were common and should be closely monitored., (Copyright © 2020. Published by Elsevier Inc.)

Acute kidney injury (AKI) has been associated with deleterious impacts on a variety of body systems. While AKI is often accompanied by dysregulation of mineral metabolism-including alterations in calcium, phosphate, vitamin D, parathyroid hormone, fibroblast growth factor 23, and klotho-its direct effects on the skeletal system of children and adolescents remain largely unexplored. In this review, the pathophysiology of dysregulated mineral metabolism in AKI and its potential effects on skeletal health are discussed, including data associating AKI with fracture risk., Competing Interests: MD reports funding from Mallinckrodt Pharmaceuticals. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hegde, Denburg and Glenn.)

Background: BK polyomavirus (BKPyV) is associated with symptomatic hemorrhagic cystitis after hematopoietic cell transplantation (HCT). Little is known about the host immune response, effectiveness of antiviral treatment, or impact of asymptomatic replication on long-term kidney function., Methods: In children and young adults undergoing allogeneic HCT, we quantified BKPyV viruria and viremia (pre-HCT and at Months 1-4, 8, 12, and 24 post-HCT) and tested associations of peak viremia ≥10 000 or viruria ≥109 copies/mL with estimated kidney function (glomerular filtration rate, eGFR) and overall survival at 2 years posttransplant. We examined the factors associated with viral clearance by Month 4, including BKPyV-specific T cells by enzyme-linked immune absorbent spot at Month 3 and cidofovir use., Results: We prospectively enrolled 193 participants (median age 10 years) and found that 18% had viremia ≥10 000 copies/mL and 45% had viruria ≥109 copies/mL in the first 3 months post-HCT. Among the 147 participants without cystitis (asymptomatic), 58 (40%) had any viremia. In the entire cohort and asymptomatic subset, having viremia ≥10 000 copies/mL was associated with a lower creatinine/cystatin C eGFR at 2 years post-HCT. Viremia ≥10 000 copies/mL was associated with a higher risk of death (adjusted hazard ratio, 2.2; 95% confidence interval, 1.1-4.2). Clearing viremia was associated with detectable BKPyV-specific T cells and having viremia <10 000 copies/mL, but not cidofovir exposure., Conclusions: Screening for BKPyV viremia after HCT identifies asymptomatic patients at risk for kidney disease and reduced survival. These data suggest potential changes to clinical practice, including prospective monitoring for BKPyV viremia to test virus-specific T cells to prevent or treat BKPyV replication., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background & Aims: It is not clear what factors affect risk of chronic kidney disease (CKD) in patients with inflammatory bowel disease (IBD); increased risk has been inconsistently associated with use of 5-aminosalicylates (5-ASAs). We aimed to calculate the relative hazard of CKD among patients with IBD, adjusted for CKD risk factors, and to determine whether IBD medications are associated with change in estimated glomerular filtration rate (eGFR)., Methods: We performed a retrospective cohort study of data from The Health Improvement Network. Patients with IBD (n = 17,807) were matched for age, sex, and practice to individuals without IBD (n = 63,466). The relative hazard of CKD, stages 3 through 5D, in patients with IBD was calculated using a Cox proportional hazards model adjusted for common CKD risk factors. We also evaluated the association of 5-ASAs, azathioprine, and methotrexate with change in eGFR using a longitudinal model., Results: After we controlled for risk factors associated with CKD, we found IBD to be associated with development of CKD in patients 16-77 years old. As patient age increased, the adjusted hazard ratio for CKD decreased monotonically, from 7.88 (95% CI, 2.56-24.19) at age 16 to 1.13 (95% CI, 1.01-1.25) at age 77. In the longitudinal analysis, exposure to 5-ASAs or methotrexate was not associated with change in eGFR, whereas azathioprine was associated with a slightly higher eGFR (0.32 mL/min/1.73 m 2 ; 95% CI, 0.16-0.48)., Conclusions: In a retrospective study of more than 80,000 persons, we found that IBD is associated with increased risk of CKD, and the hazard ratio is highest among younger patients. Commonly used non-biologic therapeutic agents were not associated with lower eGFR., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Acute kidney injury (AKI) is nearly universally associated with worse outcomes, especially among children after hematopoietic stem cell transplant (HCT). Our objective was to examine urinary immune biomarkers of AKI after HCT to provide insights into novel mechanisms of kidney injury in this population. Studying patients undergoing allogeneic HCT provides a unique opportunity to examine immune markers of AKI because the risk of AKI is high and the immune system newly develops after transplant. Children (>2 years old) and young adults undergoing their first allogeneic HCT and enrolled in a prospective, observational cohort study at 2 large children's hospitals had urine collected pre-HCT and monthly for the first 4 months after HCT. Urine samples at each monthly time point were assayed for 8 immune-related biomarkers. AKI was defined as a 1.5-fold increase in the monthly serum creatinine value, which was recorded ±1 day from when the research urine sample was obtained, as compared with the pre-HCT baseline. Generalized estimating equation regression analysis evaluated the association between the monthly repeated measures (urinary biomarkers and AKI). A total of 176 patients were included from 2 pediatric centers. Thirty-six patients from 1 center were analyzed as a discovery cohort and the remaining 140 patients from the second center were analyzed as a validation cohort. AKI rates were 18% to 35% depending on the monthly time point after HCT. Urine CXCL10 and CXCL9 concentrations were significantly higher among children who developed AKI compared with children who did not (P < .01) in both cohorts. In order to gain a better understanding of the cellular source for these biomarkers in the urine, we also analyzed in vitro expression of CXCL10 and CXCL9 in kidney cell lines after stimulation with interferon-γ and interferon-α. HEK293-epithelial kidney cells demonstrated interferon-induced expression of CXCL10 and CXCL9, suggesting a potential mechanism driving the key finding. CXCL10 and CXCL9 are associated with AKI after HCT and are therefore promising biomarkers to guide improved diagnostic and treatment strategies for AKI in this high-risk population., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Advances in cancer treatment have improved survival; however, local recurrence and metastatic disease-the principal causes of cancer mortality-have limited the ability to achieve durable remissions. Local recurrences arise from latent tumor cells that survive therapy and are often not detectable by conventional clinical imaging techniques. Local recurrence after transarterial embolization (TAE) of hepatocellular carcinoma (HCC) provides a compelling clinical correlate of this phenomenon. In response to TAE-induced ischemia, HCC cells adapt their growth program to effect a latent phenotype that precedes local recurrence., Approach and Results: In this study, we characterized and leveraged the metabolic reprogramming demonstrated by latent HCC cells in response to TAE-induced ischemia to enable their detection in vivo using dynamic nuclear polarization (DNP) magnetic resonance spectroscopic imaging (MRSI) of 13 carbon-labeled substrates. Under TAE-induced ischemia, latent HCC cells demonstrated reduced metabolism and developed a dependence on glycolytic flux to lactate. Despite the hypometabolic state of these cells, DNP-MRSI of 1- 13 C-pyruvate and its downstream metabolites, 1- 13 C-lactate and 1- 13 C-alanine, predicted histological viability., Conclusions: These studies provide a paradigm for imaging latent, treatment-refractory cancer cells, suggesting that DNP-MRSI provides a technology for this application., (© 2019 by the American Association for the Study of Liver Diseases.)

Background: The relationship between the composition and function of gut microbial communities and early-onset calcium oxalate kidney stone disease is unknown., Methods: We conducted a case-control study of 88 individuals aged 4-18 years, which included 44 individuals with kidney stones containing ≥50% calcium oxalate and 44 controls matched for age, sex, and race. Shotgun metagenomic sequencing and untargeted metabolomics were performed on stool samples., Results: Participants who were kidney stone formers had a significantly less diverse gut microbiome compared with controls. Among bacterial taxa with a prevalence >0.1%, 31 taxa were less abundant among individuals with nephrolithiasis. These included seven taxa that produce butyrate and three taxa that degrade oxalate. The lower abundance of these bacteria was reflected in decreased abundance of the gene encoding butyryl-coA dehydrogenase ( P =0.02). The relative abundance of these bacteria was correlated with the levels of 18 fecal metabolites, and levels of these metabolites differed in individuals with kidney stones compared with controls. The oxalate-degrading bacterial taxa identified as decreased in those who were kidney stone formers were components of a larger abundance correlation network that included Eggerthella lenta and several Lactobacillus species. The microbial ( α ) diversity was associated with age of stone onset, first decreasing and then increasing with age. For the individuals who were stone formers, we found the lowest α diversity among individuals who first formed stones at age 9-14 years, whereas controls displayed no age-related differences in diversity., Conclusions: Loss of gut bacteria, particularly loss of those that produce butyrate and degrade oxalate, associates with perturbations of the metabolome that may be upstream determinants of early-onset calcium oxalate kidney stone disease., (Copyright © 2020 by the American Society of Nephrology.)

Rationale & Objective: Chronic kidney disease (CKD) in children is associated with cognitive dysfunction that affects school performance and quality of life. The relationship between CKD-mineral and bone disorder and cognitive function in children is unknown., Study Design: Observational study., Participants: 702 children enrolled in the Chronic Kidney Disease in Children (CKiD) Study., Predictors: Plasma fibroblast growth factor 23 (FGF-23), parathyroid hormone (PTH), calcium, phosphorus, 25 hydroxyvitamin D (25[OH]D), and 1,25 dihydroxyvitamin D (1,25[OH] 2 D)., Outcomes: Neurocognitive tests of intelligence, academic achievement, and executive functions., Analytical Approach: Linear regression models to analyze the cross-sectional associations between log 2 FGF-23, 25(OH)D, 1,25(OH) 2 D, PTH, calcium, and phosphorus z scores and the cognitive test scores of interest after adjustment for demographics, blood pressure, proteinuria, and kidney function., Results: At baseline, median age was 12 (95% CI, 8.3, 15.2) years and estimated glomerular filtration rate was 54 (40.5, 67.8) mL/min/1.73 m 2 . In fully adjusted analyses, 25(OH)D, 1,25(OH) 2 D, PTH, calcium, and phosphorus z scores did not associate with cognitive test scores. In fully adjusted analyses, log 2 FGF-23 was associated with abnormal test scores for attention regulation ( P  < 0.05); specifically, Conners' Continuous Performance Test II Errors of Omission (β = 2.3 [1.0, 3.6]), Variability (β=1.4 [0.4, -2.4]), and Hit Reaction Time (β = 1.3 [0.2, 2.4]). Children in the highest FGF-23 tertile group had 7% and 9% greater cognitive risk for Hit Reaction Time and Errors of Omission compared with those in the lowest tertile, respectively. In fully adjusted analyses, higher FGF-23 tertile was associated with increased cognitive risk ( P  < 0.05) for Errors of Omission (β = 0.4 [0.1, 0.7]) and Hit Reaction Time (β = 0.4 [0.1, 0.7])., Limitations: The study does not assess the cumulative effects of FGF-23 excess on cognitive function over time. Within-population stratified analyses were not performed due to limited sample size., Conclusions: In children with CKD, higher plasma FGF-23 level is associated with lower performance in targeted tests of executive function, specifically attention regulation, independent of glomerular filtration rate., (© 2020 The Authors.)

To examine metabolic differences between renal allograft acute cellular rejection (ACR) and ischemic-reperfusion injury (IRI), we transplanted MHC-mismatched kidneys and induced 28 min warm-IRI, and collected the ACR and IRI kidneys as well as their respective native and collateral control kidneys. We extracted metabolites from the kidney tissues and found the lysine catabolite saccharopine 12.5-fold enriched in IRI kidneys, as well as the immunometabolites itaconate and kynurenine in ACR kidneys. Saccharopine accumulation is known to be toxic to mitochondria and may contribute to IRI pathophysiology, while itaconate and kynurenine may be reflective of counterregulatory responses to immune activation in ACR.

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

Objectives: We observed that patients treated with continuous vecuronium or esmolol infusions showed elevated plasma sodium measurements when measured by the routine chemistry analyzer as part of the basic metabolic panel (Vitros 5600; Ortho Clinical Diagnostics, Raritan, NJ), but not by blood gas analyzers (RAPIDLab 1265; Siemens, Tarrytown, NY). Both instruments use direct ion-selective electrode technology, albeit with different sodium ionophores (basic metabolic panel: methyl monensin, blood gas: glass). We questioned if the basic metabolic panel hypernatremia represents artefactual pseudohypernatremia., Design: We added vecuronium bromide or esmolol hydrochloric acid to pooled plasma samples and compared sodium values measured by both methodologies. We queried sodium results from the electronic medical records of patients admitted at Children's Hospital of Philadelphia from 2016 to 2018 and received vecuronium and/or esmolol infusion treatment during their admissions., Setting: PICU of a quaternary, free-standing children's hospital., Patients: Children admitted to the hospital who received vecuronium and/or esmolol infusion., Measurements and Main Results: Sodium was measured in pooled plasma samples by basic metabolic panel and blood gas methodologies after adding vecuronium bromide or esmolol hydrochloric acid, leading to a dose-response increase in basic metabolic panel sodium measurements. A repeated measures regression analysis of our electronic medical records showed that the vecuronium dose predicted the Δ sodium (basic metabolic panel-blood gas) sodium within 12 hours of the vecuronium administration ( p < 0.0018). Esmolol showed a similar trend ( p = 0.13). This occurred primarily in central line samples with continuous vecuronium or esmolol infusions., Conclusions: Vecuronium and esmolol can falsely elevate direct ion-selective electrode sodium measurements on Vitros chemistry analyzers. Unexpectedly high sodium measurements in patients receiving vecuronium and/or esmolol infusions should be further investigated with an alternate sample type (i.e., peripheral blood) or measurement methodology (i.e., blood gas) to guide treatment decisions., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2020 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Purpose of Review: To summarize the literature regarding alterations in bone health in patients with glomerular kidney disease and highlight areas in need of additional investigation., Recent Findings: There is mounting evidence that children and adults with glomerular conditions, with or without compromised kidney function, comprise a distinct subgroup of patients with unique risk factors for altered bone health. Patients with glomerular kidney disease are exposed to both disease-related and treatment-related factors that affect bone structure and function. In addition to chronic kidney disease-related risk factors for impaired bone health, high rates of exposure to osteotoxic medications, varying degrees of systemic inflammation, and altered vitamin D metabolism may contribute to compromised bone health in individuals with glomerular disease. Further study is needed to better understand these risk factors and the complex interaction between the immune system and bone cells in glomerular disease.

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., (Copyright © 2019 by the American Society of Nephrology.)

Introduction: Children with chronic kidney disease (CKD) risk progressing to end-stage kidney disease (ESKD). The majority of CKD causes in children are related to congenital anomalies of the kidney and urinary tract, which may be treated by urologic care., Objective: To examine the association of ESKD with urologic care in children with CKD., Study Design: This was a nested case-control study within the Chronic Kidney Disease in Children (CKiD) prospective cohort study that included children aged 1-16 years with non-glomerular causes of CKD. The primary exposure was prior urologic referral with or without surgical intervention. Incidence density sampling matched each case of ESKD to up to three controls on duration of time from CKD onset, sex, race, age at baseline visit, and history of low birth weight. Conditional logistic regression analysis was performed to estimate rate ratios (RRs) for the incidence of ESKD., Results: Sixty-six cases of ESKD were matched to 153 controls. Median age at baseline study visit was 12 years; 67% were male, and 7% were black. Median follow-up time from CKD onset was 14.9 years. Seventy percent received urologic care, including 100% of obstructive uropathy and 96% of reflux nephropathy diagnoses. Cases had worse renal function at their baseline visit and were less likely to have received prior urologic care. After adjusting for income, education, and insurance status, urology referral with surgery was associated with 50% lower risk of ESKD (RR 0.50 [95% confidence interval [CI] 0.26-0.997), compared to no prior urologic care (Figure). After excluding obstructive uropathy and reflux nephropathy diagnoses, which were highly correlated with urologic surgery, the association was attenuated (RR 0.72, 95% CI 0.24-2.18)., Discussion: In this study, urologic care was commonly but not uniformly provided to children with non-glomerular causes of CKD. Underlying specific diagnoses play an important role in both the risk of ESKD and potential benefits of urologic surgery., Conclusion: Within the CKiD cohort, children with non-glomerular causes of CKD often received urologic care. Urology referral with surgery was associated with lower risk of ESKD compared to no prior urologic care but depended on specific underlying diagnoses., (Copyright © 2019 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Background and Objectives: Nontargeted metabolomics can measure thousands of low-molecular-weight biochemicals, but important gaps limit its utility for biomarker discovery in CKD. These include the need to characterize technical and intraperson analyte variation, to pool data across platforms, and to outline analyte relationships with eGFR., Design, Setting, Participants, & Measurements: Plasma samples from 49 individuals with CKD (eGFR<60 ml/min per 1.73 m 2 and/or ≥1 g proteinuria) were examined from two study visits; 20 samples were repeated as blind replicates. To enable comparison across two nontargeted platforms, samples were profiled at Metabolon and the Broad Institute., Results: The Metabolon platform reported 837 known metabolites and 483 unnamed compounds (selected from 44,953 unknown ion features). The Broad Institute platform reported 594 known metabolites and 26,106 unknown ion features. Median coefficients of variation (CVs) across blind replicates were 14.6% (Metabolon) and 6.3% (Broad Institute) for known metabolites, and 18.9% for (Metabolon) unnamed compounds and 24.5% for (Broad Institute) unknown ion features. Median CVs for day-to-day variability were 29.0% (Metabolon) and 24.9% (Broad Institute) for known metabolites, and 41.8% for (Metabolon) unnamed compounds and 40.9% for (Broad Institute) unknown ion features. A total of 381 known metabolites were shared across platforms (median correlation 0.89). Many metabolites were negatively correlated with eGFR at P <0.05, including 35.7% (Metabolon) and 18.9% (Broad Institute) of known metabolites., Conclusions: Nontargeted metabolomics quantifies >1000 analytes with low technical CVs, and agreement for overlapping metabolites across two leading platforms is excellent. Many metabolites demonstrate substantial intraperson variation and correlation with eGFR., (Copyright © 2019 by the American Society of Nephrology.)

Objective: To determine the incidence of and risk factors for development of celiac disease (CD) in individuals with type 1 diabetes., Methods: Cohort study using The Health Improvement Network (THIN), a UK primary care database of >13 million people. Individuals with incident type 1 diabetes diagnosed at 1 to 35 years of age between 1995 and 2015 with no previous diagnosis of CD were included. Cox regression was used to identify risk factors for CD, including age at diabetes diagnosis and sex, while adjusting for year of diagnosis to control for potential rising incidence in CD over time., Results: Subjects (n = 9180; 43% female) had a median observation time of 5.1 years (interquartile range 2.0-10.1). CD was diagnosed in 196 (2%) during follow up. Median time to diagnosis was 2.1 years, but 25% were diagnosed more than 5 years after diabetes diagnosis. Incidence (per 10 000 person-years) was greater in females (43.0 [95% confidence interval [CI] 35.2-52.0]) vs males (26.8 [95% CI 21.5-32.9]). In multivariable Cox regression stratified by childhood- vs young adult-onset diabetes, younger age at diabetes diagnosis within childhood (hazard ratio [HR] 0.91 [95% CI 0.88-0.94]) and female sex among the adult-onset diabetes group (HR 3.19 [95% CI 1.39-7.34]) were associated with greater risk of CD., Conclusions: As expected, incidence of CD was higher in individuals with childhood-onset diabetes vs those with adult-onset diabetes. However, individuals with diabetes are at risk of developing CD throughout childhood and adulthood, and prolonged screening after diagnosis may be warranted. Prospective studies are needed in order to guide risk-stratified approaches to screening., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)