Post-transplant recurrence of focal segmental glomerular sclerosis: consensus statements.

Focal segmental glomerular sclerosis (FSGS) is 1 of the primary causes of nephrotic syndrome in both pediatric and adult patients, which can lead to end-stage kidney disease. Recurrence of FSGS after kidney transplantation significantly increases allograft loss, leading to morbidity and mortality. Currently, there are no consensus guidelines for identifying those patients who are at risk for recurrence or for the management of recurrent FSGS. Our work group performed a literature search on PubMed/Medline, Embase, and Cochrane, and recommendations were proposed and graded for strength of evidence. Of the 614 initially identified studies, 221 were found suitable to formulate consensus guidelines for recurrent FSGS. These guidelines focus on the definition, epidemiology, risk factors, pathogenesis, and management of recurrent FSGS. We conclude that additional studies are required to strengthen the recommendations proposed in this review.

Pubertal luteinizing hormone levels in children with chronic kidney disease and association with change in glomerular filtration rate.

BACKGROUND: Children with chronic kidney disease (CKD) are at risk for abnormalities in pubertal development. We aimed to describe the timing of pubertal onset by luteinizing hormone (LH) levels and the association between hormonal onset of puberty with changes in GFR. METHODS: Data from the Chronic Kidney Disease in Children (CKiD) study were collected prospectively. GFR was estimated at annual visits and measured by iohexol clearance every other year. LH was measured from stored repository serum samples in a nested sample of 124 participants. Hormonal onset of puberty was defined as LH level greater than or equal to 0.3 IU/L. A mixed effects model with random intercepts and slopes was used to compare the slope of decline of GFR before and after hormonal onset of puberty. The model was adjusted for age, glomerular disease diagnosis, baseline proteinuria on the log scale, and BMI. RESULTS: Median age at hormonal onset of puberty was 9.9 years (IQR 8.1, 11.9) in girls and 10.2 years (IQR 9.2, 11.0) in boys. The mixed effects model showed faster decline in both estimated GFR and measured GFR in boys after hormonal onset of puberty (p < 0.001), and a similar but attenuated accelerated estimated GFR decline was observed for girls with no difference for measured GFR. CONCLUSIONS: LH levels in the post-pubertal range were observed prior to clinical manifestations of puberty in children with CKD. Hormonal onset of puberty was associated with faster decline in GFR, particularly among boys with CKD.

Associations between anemia and FGF23 in the CKiD study.

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 < 0.001). In multivariable linear regression modeling, anemia was independently associated with higher total FGF23, after adjustment for demographic, kidney-related, mineral metabolism, and inflammatory covariables (standardized ß (95% confidence interval) 0.10 (0.04, 0.17), p = 0.002). In the subset of subjects with available iron parameters (n = 191), iron deficiency was not associated with significantly higher total FGF23 concentrations. In the subgroup that had measurements of both total and intact FGF23 (n = 185), in fully adjusted models, anemia was significantly associated with higher total FGF23 (standardized ß (95% CI) 0.16 (0.04, 0.27), p = 0.008) but not intact FGF23 (standardized ß (95% CI) 0.02 (-0.12, 0.15), p = 0.81). CONCLUSIONS: In this cohort of pediatric patients with CKD, anemia was associated with increased total FGF23 levels but was not independently associated with elevated intact FGF23, suggesting possible effects on both FGF23 production and cleavage. Further studies are warranted to investigate non-mineral factors affecting FGF23 production and metabolism in CKD.

Real-world evidence on the dosing and safety of C.E.R.A. in pediatric dialysis patients: findings from the International Pediatric Dialysis Network registries.

BACKGROUND: This retrospective real-world study used data from two registries, International Pediatric Peritoneal Dialysis Network (IPPN) and International Pediatric Hemodialysis Network (IPHN), to characterize the efficacy and safety of continuous erythropoietin receptor activator (C.E.R.A.) in pediatric patients with chronic kidney disease (CKD) on peritoneal dialysis (PD) or hemodialysis (HD). METHODS: IPPN and IPHN collect prospective data (baseline and every 6 months) from pediatric PD and HD centers worldwide. Demographics, clinical characteristics, dialysis information, treatment, laboratory parameters, number and causes of hospitalization events, and deaths were extracted for patients on C.E.R.A. treatment (IPPN: 2007-2021; IPHN: 2013-2021). RESULTS: We analyzed 177 patients on PD (median age 10.6 years) and 52 patients on HD (median age 14.1 years) who had ≥ 1 observation while being treated with C.E.R.A. The median (interquartile range [IQR]) observation time under C.E.R.A. exposure was 6 (0-12.5) and 12 (0-18) months, respectively. Hemoglobin concentrations were stable over time; respective means (standard deviation) at last observation were 10.9 (1.7) g/dL and 10.4 (1.7) g/dL. Respective median (IQR) monthly C.E.R.A. doses at last observation were 3.5 (2.3-5.1) µg/kg, or 95 (62-145) µg/m2 and 2.1 (1.2-3.4) µg/kg, or 63 (40-98) µg/m2. Non-elective hospitalizations occurred in 102 (58%) PD and 32 (62%) HD patients. Seven deaths occurred (19.8 deaths per 1000 observation years). CONCLUSIONS: C.E.R.A. was associated with efficient maintenance of hemoglobin concentrations in pediatric patients with CKD on dialysis, and appeared to have a favorable safety profile. The current analysis revealed no safety signals.

Use of ClearGuard HD caps in pediatric hemodialysis patients.

BACKGROUND: Bloodstream infections (BSIs) are a leading cause of hospitalizations and mortality among patients receiving hemodialysis (HD) therapy, especially those with a central venous catheter (CVC) for dialysis access. The use of chlorhexidine impregnated catheter caps (ClearGuard) has been associated with a decrease in the rate of HD catheter-related BSIs (CA-BSIs) in adults; similar data have not been published for children. METHODS: We compared CA-BSI data from participating centers within the Standardizing Care to Improve Outcomes in Pediatric Endstage Kidney Disease (SCOPE) collaborative based on the center's use of ClearGuard caps for patients with HD catheter access. Centers were characterized as ClearGuard (CG) or non-ClearGuard (NCG) centers, with CA-BSI data pre- and post-CG implementation reviewed. All positive blood cultures in participating centers were reported to the SCOPE collaborative and adjudicated by an infectious disease physician. RESULTS: Data were available from 1786 SCOPE enrollment forms completed January 2016-January 2022. January 2020 served as the implementation date for analyzing CG versus NCG center data, with this being the time when the last CG center underwent implementation. Post January 2020, there was a greater decrease in the rate of HD CA-BSI in CG centers versus NCG centers, with a decrease from 1.18 to 0.23 and 0.41 episodes per 100 patient months for the CG and NCG centers, respectively (p = 0.002). CONCLUSIONS: Routine use of ClearGuard caps in pediatric dialysis centers was associated with a reduction of HD CA-BSI rates in pediatric HD patients.

Assessment and management of vitamin status in children with CKD stages 2-5, on dialysis and post-transplantation: clinical practice points from the Pediatric Renal Nutrition Taskforce.

Children with chronic kidney disease (CKD) are at risk for vitamin deficiency or excess. Vitamin status can be affected by diet, supplements, kidney function, medications, and dialysis. Little is known about vitamin requirements in CKD, leading to practice variation.The Pediatric Renal Nutrition Taskforce (PRNT), an international team of pediatric kidney dietitians and pediatric nephrologists, was established to develop evidence-based clinical practice points (CPPs) to address challenges and to serve as a resource for nutritional care. Questions were formulated using PICO (Patient, Intervention, Comparator, Outcomes), and literature searches undertaken to explore clinical practice from assessment to management of vitamin status in children with CKD stages 2-5, on dialysis and post-transplantation (CKD2-5D&T). The CPPs were developed and finalized using a Delphi consensus approach. We present six CPPs for vitamin management for children with CKD2-5D&T. We address assessment, intervention, and monitoring. We recommend avoiding supplementation of vitamin A and suggest water-soluble vitamin supplementation for those on dialysis. In the absence of evidence, a consistent structured approach to vitamin management that considers assessment and monitoring from dietary, physical, and biochemical viewpoints is needed. Careful consideration of the impact of accumulation, losses, comorbidities, and medications needs to be explored for the individual child and vitamin before supplementation can be considered. When supplementing, care needs to be taken not to over-prescribe. Research recommendations are suggested.

Plasma Metabolomics of Dietary Intake of Protein-Rich Foods and Kidney Disease Progression in Children.

OBJECTIVE: Evidence regarding the efficacy of a low-protein diet for patients with CKD is inconsistent and recommending a low-protein diet for pediatric patients is controversial. There is also a lack of objective biomarkers of dietary intake. The purpose of this study was to identify plasma metabolites associated with dietary intake of protein and to assess whether protein-related metabolites are associated with CKD progression. METHODS: Nontargeted metabolomics was conducted in plasma samples from 484 Chronic Kidney Disease in Children (CKiD) participants. Multivariable linear regression estimated the cross-sectional association between 949 known, nondrug metabolites and dietary intake of total protein, animal protein, plant protein, chicken, dairy, nuts and beans, red and processed meat, fish, and eggs, adjusting for demographic, clinical, and dietary covariates. Cox proportional hazards models assessed the prospective association between protein-related metabolites and CKD progression defined as the initiation of kidney replacement therapy or 50% eGFR reduction, adjusting for demographic and clinical covariates. RESULTS: One hundred and twenty-seven (26%) children experienced CKD progression during 5 years of follow-up. Sixty metabolites were significantly associated with dietary protein intake. Among the 60 metabolites, 10 metabolites were significantly associated with CKD progression (animal protein: n = 1, dairy: n = 7, red and processed meat: n = 2, nuts and beans: n = 1), including one amino acid, one cofactor and vitamin, 4 lipids, 2 nucleotides, one peptide, and one xenobiotic. 1-(1-enyl-palmitoyl)-2-oleoyl-glycerophosphoethanolamine (GPE, P-16:0/18:1) was positively associated with dietary intake of red and processed meat, and a doubling of its abundance was associated with 88% higher risk of CKD progression. 3-ureidopropionate was inversely associated with dietary intake of red and processed meat, and a doubling of its abundance was associated with 48% lower risk of CKD progression. CONCLUSIONS: Untargeted plasma metabolomic profiling revealed metabolites associated with dietary intake of protein and CKD progression in a pediatric population.

The management of dietary fiber intake in children with chronic kidney disease - clinical practice recommendations from the Pediatric Renal Nutrition Taskforce.

The benefits of dietary fiber are widely accepted. Nevertheless, a substantial proportion of children fail to meet the recommended intake of dietary fiber. Achieving adequate fiber intake is especially challenging in children with chronic kidney disease (CKD). An international team of pediatric renal dietitians and pediatric nephrologists from The Pediatric Renal Nutrition Taskforce (PRNT) has developed clinical practice recommendations (CPRs) for the dietary intake of fiber in children and adolescents with CKD. In this CPR paper, we propose a definition of fiber, provide advice on the requirements and assessment of fiber intake, and offer practical guidance on optimizing dietary fiber intake in children with CKD. In addition, given the paucity of available evidence and to achieve consensus from international experts, a Delphi survey was performed in which all the clinical practice recommendations were reviewed.

Genomic Disorders in CKD across the Lifespan.

SIGNIFICANCE STATEMENT: Pathogenic structural genetic variants, also known as genomic disorders, have been associated with pediatric CKD. This study extends those results across the lifespan, with genomic disorders enriched in both pediatric and adult patients compared with controls. In the Chronic Renal Insufficiency Cohort study, genomic disorders were also associated with lower serum Mg, lower educational performance, and a higher risk of death. A phenome-wide association study confirmed the link between kidney disease and genomic disorders in an unbiased way. Systematic detection of genomic disorders can provide a molecular diagnosis and refine prediction of risk and prognosis. BACKGROUND: Genomic disorders (GDs) are associated with many comorbid outcomes, including CKD. Identification of GDs has diagnostic utility. METHODS: We examined the prevalence of GDs among participants in the Chronic Kidney Disease in Children (CKiD) cohort II ( n =248), Chronic Renal Insufficiency Cohort (CRIC) study ( n =3375), Columbia University CKD Biobank (CU-CKD; n =1986), and the Family Investigation of Nephropathy and Diabetes (FIND; n =1318) compared with 30,746 controls. We also performed a phenome-wide association analysis (PheWAS) of GDs in the electronic MEdical Records and GEnomics (eMERGE; n =11,146) cohort. RESULTS: We found nine out of 248 (3.6%) CKiD II participants carried a GD, replicating prior findings in pediatric CKD. We also identified GDs in 72 out of 6679 (1.1%) adult patients with CKD in the CRIC, CU-CKD, and FIND cohorts, compared with 199 out of 30,746 (0.65%) GDs in controls (OR, 1.7; 95% CI, 1.3 to 2.2). Among adults with CKD, we found recurrent GDs at the 1q21.1, 16p11.2, 17q12, and 22q11.2 loci. The 17q12 GD (diagnostic of renal cyst and diabetes syndrome) was most frequent, present in 1:252 patients with CKD and diabetes. In the PheWAS, dialysis and neuropsychiatric phenotypes were the top associations with GDs. In CRIC participants, GDs were associated with lower serum magnesium, lower educational achievement, and higher mortality risk. CONCLUSION: Undiagnosed GDs are detected both in children and adults with CKD. Identification of GDs in these patients can enable a precise genetic diagnosis, inform prognosis, and help stratify risk in clinical studies. GDs could also provide a molecular explanation for nephropathy and comorbidities, such as poorer neurocognition for a subset of patients.

Does kidney transplant improve health-related quality of life for youth with chronic kidney disease?

Youth with chronic kidney disease are known to have impaired health-related quality of life (HRQOL), particularly as the disorder increases in severity. Few prospective, longitudinal investigations of HRQOL within the context of pediatric chronic kidney disease exist. In the current issue, Guha et al. provide a longitudinal assessment of HRQOL for a cohort of youth with chronic kidney disease. Their findings suggest that children may experience meaningful improvement in HRQOL when they transition from dialysis to transplant.

Development of an adaptive clinical web-based prediction tool for kidney replacement therapy in children with chronic kidney disease.

Clinicians need improved prediction models to estimate time to kidney replacement therapy (KRT) for children with chronic kidney disease (CKD). Here, we aimed to develop and validate a prediction tool based on common clinical variables for time to KRT in children using statistical learning methods and design a corresponding online calculator for clinical use. Among 890 children with CKD in the Chronic Kidney Disease in Children (CKiD) study, 172 variables related to sociodemographics, kidney/cardiovascular health, and therapy use, including longitudinal changes over one year were evaluated as candidate predictors in a random survival forest for time to KRT. An elementary model was specified with diagnosis, estimated glomerular filtration rate and proteinuria as predictors and then random survival forest identified nine additional candidate predictors for further evaluation. Best subset selection using these nine additional candidate predictors yielded an enriched model additionally based on blood pressure, change in estimated glomerular filtration rate over one year, anemia, albumin, chloride and bicarbonate. Four additional partially enriched models were constructed for clinical situations with incomplete data. Models performed well in cross-validation, and the elementary model was then externally validated using data from a European pediatric CKD cohort. A corresponding user-friendly online tool was developed for clinicians. Thus, our clinical prediction tool for time to KRT in children was developed in a large, representative pediatric CKD cohort with an exhaustive evaluation of potential predictors and supervised statistical learning methods. While our models performed well internally and externally, further external validation of enriched models is needed.

Validation of a prediction system for risk of kidney allograft failure in pediatric kidney transplant recipients: An international observational study.

Predicting long-term kidney allograft failure is an unmet need for clinical care and clinical trial optimization in children. We aimed to validate a kidney allograft failure risk prediction system in a large international cohort of pediatric kidney transplant recipients. Patients from 20 centers in Europe and the United States, transplanted between 2004 and 2017, were included. Allograft assessment included estimated glomerular filtration rate, urine protein-to-creatinine ratio, circulating antihuman leukocyte antigen donor-specific antibody, and kidney allograft histology. Individual predictions of allograft failure were calculated using the integrative box (iBox) system. Prediction performances were assessed using discrimination and calibration. The allograft evaluations were performed in 706 kidney transplant recipients at a median time of 9.1 (interquartile range, 3.3-19.2) months posttransplant; mean estimated glomerular filtration rate was 68.7 ± 28.1 mL/min/1.73 m2, and median urine protein-to-creatinine ratio was 0.1 (0.0-0.4) g/g, and 134 (19.0%) patients had antihuman leukocyte antigen donor-specific antibodies. The iBox exhibited accurate calibration and discrimination for predicting the outcomes up to 10 years after evaluation, with a C-index of 0.81 (95% confidence interval, 0.75-0.87). This study confirms the generalizability of the iBox to predict long-term kidney allograft failure in children, with performances similar to those reported in adults. These results support the use of the iBox to improve patient monitoring and facilitate clinical trials in children.

Subcutaneous C.E.R.A. for the Maintenance Treatment of Anemia in Pediatric Patients With CKD: A Phase 2, Open-Label, Single-Arm, Multicenter Study.

RATIONALE & OBJECTIVE: The optimum starting dose of intravenous continuous erythropoietin receptor activator (C.E.R.A.) has been previously determined; this study ascertains the optimum starting dose of subcutaneous C.E.R.A. administration in pediatric patients. STUDY DESIGN: Phase 2, open-label, single-arm, multicenter study. SETTING & PARTICIPANTS: Patients aged 3 months to 17 years with renal anemia and chronic kidney disease (CKD; including those treated with maintenance dialysis and those not treated with dialysis) who were receiving maintenance treatment with erythropoiesis-stimulating agents (ESAs). INTERVENTION: Subcutaneous C.E.R.A. administration every 4 weeks (starting dose was based on defined conversion factors). OUTCOME: The primary outcome was the change in hemoglobin concentration between the baseline and evaluation period for each patient. Secondary efficacy measures and safety were also evaluated. RESULTS: Forty patients aged 0.4-17.7 years were enrolled. The study achieved its primary outcome: the mean change in hemoglobin concentration was an increase of 0.48g/dL; the 95% confidence interval (0.15-0.82) and standard deviation (±1.03) were within the prespecified boundaries (-1 to 1g/dL and<1.5g/dL, respectively). Mean hemoglobin concentrations were maintained within the target 10-12g/dL range in 24 of 38 patients and within±1g/dL of the baseline in 19 of 38 patients, and the median C.E.R.A. subcutaneous dose decreased over time. Efficacy in key subgroups (age group, dialysis type, prior ESA treatment) was consistent with the primary outcome. Thirty-eight patients completed the core period; 25 chose to enter the safety extension period. Safety was consistent with prior studies, with no new signals. LIMITATIONS: Single-arm and open-label study; small sample size. CONCLUSIONS: Pediatric patients with anemia secondary to CKD who were on, or not on, dialysis could be safely and effectively switched from maintenance ESAs to subcutaneous C.E.R.A. administered every 4 weeks, using defined dose-conversion factors to determine the optimum starting dose. FUNDING: F. Hoffmann-La Roche Ltd. TRIAL REGISTRATION: The SKIPPER trial registered at ClinicalTrials.gov with study number NCT03552393. PLAIN-LANGUAGE SUMMARY: Anemia, a complication of chronic kidney disease, is associated with poor quality of life and an increased risk of hospitalization and mortality. The current treatments for anemia include iron therapy and erythropoiesis-stimulating agents (ESAs); however, the relatively short half-lives of the ESAs epoetin alfa/beta or darbepoetin alfa may require more frequent dosing and hospital visits compared with the ESA known as continuous erythropoietin receptor activator (C.E.R.A.). A previous study demonstrated that children aged 5 years or more with anemia associated with chronic kidney disease who were on hemodialysis could be switched to intravenous C.E.R.A. from their existing epoetin alfa/beta or darbepoetin alfa treatment. This study provides evidence that subcutaneous C.E.R.A. can safely and effectively treat anemia in children, including those aged<5 years and regardless of whether they were on dialysis or the type of dialysis they received (peritoneal dialysis or hemodialysis).

Longitudinal Relationship Between Anemia and Statural Growth Impairment in Children and Adolescents With Nonglomerular CKD: Findings From the Chronic Kidney Disease in Children (CKiD) Study.

RATIONALE & OBJECTIVE: Anemia and statural growth impairment are both prevalent in children with nonglomerular chronic kidney disease (CKD) and are associated with poor quality of life and increased morbidity and mortality. However, to date no longitudinal studies have demonstrated a relationship between anemia and statural growth in this population. STUDY DESIGN: The CKD in Children (CKiD) study is a multicenter prospective cohort study with over 15 years of follow-up observation. SETTING & PARTICIPANTS: CKiD participants younger than 22 years with nonglomerular CKD who had not reached final adult height. EXPOSURE: Age-, sex-, and race-specific hemoglobin z score. OUTCOME: Age- and sex-specific height z score. ANALYTICAL APPROACH: The relationship between hemoglobin and height was quantified using (1) multivariable repeated measures paired person-visit analysis, and (2) multivariable repeated measures linear mixed model analysis. Both models were adjusted for age, sex, body mass index, estimated glomerular filtration rate, acidosis, and medication use. RESULTS: Overall, 67% of the 510 participants studied had declining hemoglobin z score trajectories over the follow-up period, which included 1,763 person-visits. Compared with average hemoglobin z scores of≥0, average hemoglobin z scores of less than -1.0 were independently associated with significant growth impairment at the subsequent study visit, with height z score decline ranging from 0.24 to 0.35. Importantly, in 50% of cases hemoglobin z scores of less than -1.0 corresponded to hemoglobin values higher than those used as cutoffs defining anemia in the KDIGO clinical practice guideline for anemia in CKD. When stratified by age, the magnitude of the association peaked in participants aged 9 years. In line with paired-visit analyses, our mixed model analysis demonstrated that in participants with baseline hemoglobin z score less than -1.0, a hemoglobin z score decline over the follow-up period was associated with a statistically significant concurrent decrease in height z score. LIMITATIONS: Limited ability to infer causality. CONCLUSIONS: Hemoglobin decline is associated with growth impairment over time in children with mild to moderate nonglomerular CKD, even before hemoglobin levels reach the cutoffs that are currently used to define anemia in this population.

Blood Pressure Classification Status in Children With CKD Following Adoption of the 2017 American Academy of Pediatrics Guideline.

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

Identification of Novel Genetic Risk Factors for Focal Segmental Glomerulosclerosis in Children: Results From the Chronic Kidney Disease in Children (CKiD) Cohort.

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

Improving Clinical Care for Children With CKD: A Report From a National Kidney Foundation Scientific Workshop.

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.

Patient-Reported Outcomes Over 24 Months in Pediatric CKD: Findings From the MyKidneyHealth Cohort Study.

RATIONALE & OBJECTIVE: The lived experience of children with chronic kidney disease (CKD) is poorly characterized. We examined the associations between patient-reported outcome (PRO) scores measuring their fatigue, sleep health, psychological distress, family relationships, and global health with clinical outcomes over time in children, adolescents, and younger adults with CKD and investigated how the PRO scores of this group compare with those of other children, adolescents, and younger adults. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 212 children, adolescentss, and adults aged 8 to 21 years with CKD and their parents recruited from 16 nephrology programs across North America. PREDICTORS: CKD stage, disease etiology, and sociodemographic and clinical variables. OUTCOME: PRO scores over 2 years. ANALYTICAL APPROACH: We compared PRO scores in the CKD sample with a nationally representative general pediatric population (ages 8 to 17 years). Change of PROs over time and association of sociodemographic and clinical variables with PROs were assessed using multivariable regression models. RESULTS: For all time points, 84% of the parents and 77% of the children, adolescents, and younger adults completed PRO surveys . The baseline PRO scores for the participants with CKD revealed a higher burden of fatigue, sleep-related impairment, psychological distress, impaired global health, and poorer family relationships compared with the general pediatric population, with median score differences≥1 SD for fatigue and global health. The baseline PRO scores did not differ by CKD stage or glomerular versus nonglomerular etiology. Over 2 years, PROs were stable with a<1-point annual change on average on each measure and intraclass correlation coefficients ranging from 0.53 to 0.79, indicating high stability. Hospitalization and parent-reported sleep problems were associated with worse fatigue, psychological health, and global health scores (all P<0.04). LIMITATIONS: We were unable to assess responsiveness to change with dialysis or transplant. CONCLUSIONS: Children with CKD experience a high yet stable burden of impairment across numerous PRO measures, especially fatigue and global health, independent of disease severity. These findings underscore the importance of assessing PROs, including fatigue and sleep measures, in this vulnerable population. PLAIN-LANGUAGE SUMMARY: Children with chronic kidney disease (CKD) have many treatment demands and experience many systemic effects. How CKD impacts the daily life of a child is poorly understood. We surveyed 212 children, adolescents, and younger adults with CKD and their parents over 24 months to assess the participants' well-being over time. Among children, adolescents, and younger adults with CKD we found a very high and persistent burden of psychological distress that did not differ by degree of CKD or type of kidney disease. The participants with CKD endorsed greater impairment in fatigue and global health compared with healthy children, adolescents, and younger adults, and parent-reported sleep problems were associated with poorer patient-reported outcome (PRO) scores across all domains. These findings emphasize the importance of including PRO measures, including fatigue and sleep measures, into routine clinical care to optimize the lived experience of children with CKD.

Humoral and cellular response to the COVID-19 vaccine in immunocompromised children.

BACKGROUND: A suboptimal response to the 2-dose COVID-19 vaccine series in the immunocompromised population prompted recommendations for a 3rd primary dose. We aimed to determine the humoral and cellular immune response to the 3rd COVID-19 vaccine in immunocompromised children. METHODS: Prospective cohort study of immunocompromised participants, 5-21 years old, who received 2 prior doses of an mRNA COVID-19 vaccine. Humoral and CD4/CD8 T-cell responses were measured to SARS-CoV-2 spike antigens prior to receiving the 3rd vaccine dose and 3-4 weeks after the 3rd dose was given. RESULTS: Of the 37 participants, approximately half were solid organ transplant recipients. The majority (86.5%) had a detectable humoral response after the 2nd and 3rd vaccine doses, with a significant increase in antibody levels after the 3rd dose. Positive T-cell responses increased from being present in 86.5% to 100% of the cohort after the 3rd dose. CONCLUSIONS: Most immunocompromised children mount a humoral and cellular immune response to the 2-dose COVID-19 vaccine series, which is significantly augmented after receiving the 3rd vaccine dose. This supports the utility of the 3rd vaccine dose and the rationale for ongoing emphasis for vaccination against COVID-19 in this population. IMPACT: Most immunocompromised children mount a humoral and cellular immune response to the 2-dose COVID-19 vaccine series, which is significantly augmented after receiving the 3rd vaccine dose. This is the first prospective cohort study to analyze both the humoral and T-cell immune response to the 3rd COVID-19 primary vaccine dose in children who are immunocompromised. The results of this study support the utility of the 3rd vaccine dose and the rationale for ongoing emphasis for vaccination against COVID-19 in the immunosuppressed pediatric population.

Glucose Derivative Induced Vasculopathy in Children on Chronic Peritoneal Dialysis.

[Figure: see text].