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Hypertension in pediatric kidney transplant recipients contributes to long-term graft loss, yet treatment options-including angiotensin-converting enzyme inhibitors-are poorly characterized in this vulnerable population. We conducted a multicenter, open-label pharmacokinetic (PK) study of daily oral lisinopril in 22 children (ages 7-17 years) with stable kidney transplant function. Standard noncompartmental PK analyses were performed at steady state. Effects on blood pressure were examined in lisinopril-naïve patients ( n = 13). Oral clearance declined in proportion to underlying kidney function; however, in patients with low estimated glomerular filtration rate (30-59 ml/min per 1.73m2), exposure (standardized to 0.1 mg/kg/day dose) was within the range reported previously in children without a kidney transplant. In lisinopril-naïve patients, 85% and 77% had a ≥ 6 mmHg reduction in systolic and diastolic blood pressure, respectively. Lisinopril was well tolerated. Our study provides initial insight on lisinopril use in children with a kidney transplant, including starting dose considerations. [ABSTRACT FROM AUTHOR]

Background: Patients with primary focal segmental glomerulosclerosis (FSGS) resistant to current treatment regimens are at high risk of progression to end-stage kidney disease. Antifibrotic agents, such as tumor necrosis factor alpha antagonists, are a promising strategy to slow or halt the decline in renal function, based on preclinical and clinical data.Study Design: Phase 1 clinical trial to assess the pharmacokinetics, tolerability, and safety of adalimumab, a human monoclonal antibody to tumor necrosis factor alpha.Setting& Participants: 10 patients (4 male and 6 female) aged 16.8 +/- 9.0 years with an estimated glomerular filtration rate of 105 +/- 50 mL/min/1.73 m(2) were studied.Intervention: Adalimumab, 24 mg/m(2), every 14 days for 16 weeks (total, 9 doses).Outcomes: Pharmacokinetic assessment, tolerability, and safety.Measurements: Estimated glomerular filtration rate, proteinuria, and pharmacokinetic assessment after initial dosing and steady state.Results: Pharmacokinetic evaluation indicated that the area under the curve was decreased by 54% (P < 0.001) and clearance was increased by 160% (P < 0.01) in patients with resistant FSGS compared with healthy controls and patients with rheumatoid arthritis. Adalimumab was well tolerated with no serious adverse events or infectious complications attributable to the drug. Proteinuria decreased by > or = 50% in 4 of 10 treated patients.Limitations: Insufficient power to assess the safety or efficacy of adalimumab therapy for patients with resistant FSGS.Conclusions: Pharmacokinetic assessment showed increased clearance of adalimumab in patients with resistant primary FSGS and validated the need to evaluate the disposition of novel therapies for this disease to define appropriate dosing regimens. The study provides a rationale to evaluate the efficacy of adalimumab as an antifibrotic agent for resistant FSGS in phase 2/3 clinical trials. [ABSTRACT FROM AUTHOR]

Primary focal segmental glomerulosclerosis (FSGS) is a disease with poor prognosis and high unmet therapeutic need. Here, we evaluated the safety and pharmacokinetics of single-dose infusions of fresolimumab, a human monoclonal antibody that inactivates all forms of transforming growth factor-β (TGF-β), in a phase I open-label, dose-ranging study. Patients with biopsy-confirmed, treatment-resistant, primary FSGS with a minimum estimated glomerular filtration rate (eGFR) of 25  ml/min per 1.73  m(2), and a urine protein to creatinine ratio over 1.8  mg/mg were eligible. All 16 patients completed the study in which each received one of four single-dose levels of fresolimumab (up to 4  mg/kg) and was followed for 112 days. Fresolimumab was well tolerated with pustular rash the only adverse event in two patients. One patient was diagnosed with a histologically confirmed primitive neuroectodermal tumor 2 years after fresolimumab treatment. Consistent with treatment-resistant FSGS, there was a slight decline in eGFR (median decline baseline to final of 5.85 ml/min per 1.73  m(2)). Proteinuria fluctuated during the study with the median decline from baseline to final in urine protein to creatinine ratio of 1.2  mg/mg with all three Black patients having a mean decline of 3.6  mg/mg. The half-life of fresolimumab was ∼14 days, and the mean dose-normalized Cmax and area under the curve were independent of dose. Thus, single-dose fresolimumab was well tolerated in patients with primary resistant FSGS. Additional evaluation in a larger dose-ranging study is necessary. [ABSTRACT FROM AUTHOR]

Here, using natural hematoxylin (HT) as linker, metal-organic frameworks (MOFs) from Cu(II), Fe(II), and Fe(III) ions was prepared. The SEM images and DLS analyses revealed HT-based MOFs are 2 /g for HT-Fe(III) MOFs. Interestingly, HT-based MOFs exhibit fluorescent properties at λ em =330 nm with fluorescence intensities of 11485, 2120, and 6790 (a.u) for HT-Cu(II), Fe(II), and Fe(III) MOFs, respectively. Moreover, HT-based MOFs inhibited α-glucosidase enyzme in a concentration-dependent manner e. g., 33.1 %, 69.8 %, and 59.7 % of C enzyme =500 mg/mL was inhibited by HT-Cu(II)-MOF, HT-Fe(II)-MOF, and HT-Fe(III)-MOFs, respectively. The minimum bactericidal concentration (MBC) values of HT-Cu(II) MOFs for Escherichia coli (gram -), Staphylococcus aureus (gram +), and Candida albicans are determined as 5, 5, and 10 mg/mL, respectively. Also, the antioxidant activities of 250 ppm HT-based MOF based on total phenol content (TPC) tests revealed 279, 208, 124, and 152 mg.gallic acid equivalent/mL (mg GA equivalency/mL) for HT, HT-Cu(II) MOF, HT-Fe(II) MOF, and HT-Fe(III), respectively affirming that antioxidant properties were retained. Moreover, HT-Fe(II) and HT-Fe(III) MOFs (62.5 μg/mL) against human null-1 lung cell line revealed cell viabilities of 98.7±12.2 % and 88.9±11.7 %, respectively as concentration-dependent biocompatibility of MOFs., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Background: Steroids, the mainstay of treatment for nephrotic syndrome in children, have multiple adverse effects including growth suppression., Methods: Anthropometric measurements in children < 18 years enrolled in the Nephrotic Syndrome Study Network (NEPTUNE) were collected. The longitudinal association of medication exposure and nephrotic syndrome characteristics with height z-score and growth velocity was determined using adjusted Generalized Estimating Equation regression and linear regression., Results: A total of 318 children (57.2% males) with a baseline age of 7.64 ± 5.04 years were analyzed. The cumulative steroid dose was 216.4 (IQR 61.5, 652.7) mg/kg (N = 233). Overall, height z-scores were not significantly different at the last follow-up compared to baseline (- 0.13 ± 1.21 vs. - 0.23 ± 1.71, p = 0.21). In models adjusted for age, sex, and eGFR, greater cumulative steroid exposure (β - 7.5 × 10 -6 , CI - 1.2 × 10 -5 , - 3 × 10 -6 , p = 0.001) and incident cases of NS (vs. prevalent) (β - 1.1, CI - 2.22, - 0.11, p = 0.03) were significantly associated with lower height z-scores over time. Rituximab exposure was associated with higher height z-scores (β 0.16, CI 0.04, 0.29, p = 0.01) over time., Conclusion: Steroid dose was associated with lower height z-score, while rituximab use was associated with higher height z-score., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Primary glomerular diseases are rare entities. This has hampered efforts to better understand the underlying pathobiology and to develop novel safe and effective therapies. NEPTUNE is a rare disease network that is focused on patients of all ages with minimal change disease, focal segmental glomerulosclerosis, and membranous nephropathy. It is a longitudinal cohort study that collects detailed demographic, clinical, histopathologic, genomic, transcriptomic, and metabolomic data. The goal is to develop a molecular classification for these disorders that supersedes the traditional pathological features-based schema. Pediatric patients are important contributors to this ongoing project. In this review, we provide a snapshot of the children and adolescents enrolled in NEPTUNE and summarize some key observations that have been made based on the data accumulated during the study. In addition, we describe the development of NEPTUNE Match, a program that aims to leverage the multi-scalar information gathered for each individual patient to provide guidance about potential clinical trial participation based on the molecular characterization and non-invasive biomarker profile. This represents the first organized effort to apply principles of precision medicine to the treatment of patients with primary glomerular disease. NEPTUNE has proven to be an invaluable asset in the study of glomerular diseases in patients of all ages including children and adolescents., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Background: In the current study, longitudinal BP and lipid measurements were examined in a NEPTUNE cohort of children with newly diagnosed nephrotic syndrome (cNEPTUNE). We hypothesized that hypertensive BP and dyslipidemia would persist in children with nephrotic syndrome, regardless of steroid treatment response., Methods: A multi-center longitudinal observational analysis of data obtained from children < 19 years of age with new onset nephrotic syndrome enrolled in the Nephrotic Syndrome Study Network (cNEPTUNE) was conducted. BP and lipid data were examined over time stratified by disease activity and steroid exposure. Generalized estimating equation regressions were used to find determinants of hypertensive BP and dyslipidemia., Results: Among 122 children, the prevalence of hypertensive BP at any visit ranged from 17.4% to 57.4%, while dyslipidemia prevalence ranged from 40.0% to 96.2% over a median of 30 months of follow-up. Hypertensive BP was found in 46.2% (116/251) of study visits during active disease compared with 31.0% (84/271) of visits while in remission. Dyslipidemia was present in 88.2% (120/136) of study visits during active disease and in 66.0% (101/153) while in remission. Neither dyslipidemia nor hypertensive BP were significantly different with/without medication exposure (steroids and/or CNI). In regression analysis, male sex and urine protein:creatinine ratio (UPC) were significant determinants of hypertensive BP over time, while eGFR was found to be a determinant of dyslipidemia over time., Conclusions: Results demonstrate persistent hypertensive BPs and unfavorable lipid profiles in the cNEPTUNE cohort regardless of remission status or concurrent steroid or calcineurin inhibitor treatment., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Significance Statement: ESKD incidence has changed substantially in the past four decades, but differences by age and race have been unexplored. Using data from the United States Renal Data System, we found that ESKD incidence rose for Black and White teenagers, adults, and older adults for two decades beginning in 1980. Growth in incidence slowed for most groups by 1993, and by 2006, the annual percent change (APC) in ESKD incidence had declined for all groups, except White adults, for whom rates continued to rise. By 2019, ESKD incidence among Black and White adolescents nearly returned to 1980 levels, but no other group achieved that degree of improvement. Nonetheless, the ESKD incidence rate among Black American patients exceeds that of White patients in every age group. Distinct patterns in ESKD incidence among patients of different age, sex, and racial groups are shown. These findings could reflect changes in dialysis acceptance rates, access to preventive health care, incidence of diabetes mellitus, implementation of evidence-based guidelines for treatment of CKD, or other unrecognized factors. There may be population-specific opportunities to change the growth of the US ESKD population and address current racial disparities., Background: Substantial changes in ESKD incidence over four decades among Black and White Americans of different ages have been incompletely explored., Methods: We analyzed United States Renal Data System data from 1980 to 2019 to determine ESKD incidence trends among Black and White adolescent (13-17 years), adult (18-64 years), and older adult (≥65) populations. We used the National Cancer Institute Joinpoint Regression Program to estimate annual percent change (APC) in ESKD incidence and to define points in time where a statistically significant change in APC slope occurred for each group., Results: ESKD incidence rose after 1980 for all groups, although the trends differed ( P < 0.001). Growth in incidence slowed for most by 1993, and by 2006, the APC in ESKD incidence had declined for all groups, except White adults, for whom rates continued to rise ( P < 0.05). By 2019, ESKD incidence among Black and White adolescents nearly returned to 1980 levels, but no other group achieved that degree of improvement. Nonetheless, the ESKD incidence among Black American patients exceeds that of White patients in every age group., Conclusions: Distinct patterns in ESKD incidence among patients of different age, sex, and racial groups are shown. These findings could reflect changes in dialysis acceptance rates, access to preventive health care, incidence of diabetes mellitus, implementation of evidence-based guidelines for treatment of CKD, or other unrecognized factors., Podcast: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2024&#95;03&#95;13&#95;ASN0000000000000310.mp3., (Copyright © 2024 by the American Society of Nephrology.)

Despite clinical use of immunosuppressive agents, the immunopathogenesis of minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) remains unclear. Src homology 3-binding protein 2 (SH3BP2), a scaffold protein, forms an immune signaling complex (signalosome) with 17 other proteins, including phospholipase Cγ2 (PLCγ2) and Rho-guanine nucleotide exchange factor VAV2 (VAV2). Bioinformatic analysis of human glomerular transcriptome (Nephrotic Syndrome Study Network cohort) revealed upregulated SH3BP2 in MCD and FSGS. The SH3BP2 signalosome score and downstream MyD88, TRIF, and NFATc1 were significantly upregulated in MCD and FSGS. Immune pathway activation scores for Toll-like receptors, cytokine-cytokine receptor, and NOD-like receptors were increased in FSGS. Lower SH3BP2 signalosome score was associated with MCD, higher estimated glomerular filtration rate, and remission. Further work using Sh3bp2KI/KI transgenic mice with a gain-in-function mutation showed ~6-fold and ~25-fold increases in albuminuria at 4 and 12 weeks, respectively. Decreased serum albumin and unchanged serum creatinine were observed at 12 weeks. Sh3bp2KI/KI kidney morphology appeared normal except for increased mesangial cellularity and patchy foot process fusion without electron-dense deposits. SH3BP2 co-immunoprecipitated with PLCγ2 and VAV2 in human podocytes, underscoring the importance of SH3BP2 in immune activation. SH3BP2 and its binding partners may determine the immune activation pathways resulting in podocyte injury leading to loss of the glomerular filtration barrier.

Glomerular diseases are classified using a descriptive taxonomy that is not reflective of the heterogeneous underlying molecular drivers. This limits not only diagnostic and therapeutic patient management, but also impacts clinical trials evaluating targeted interventions. The Nephrotic Syndrome Study Network (NEPTUNE) is poised to address these challenges. The study has enrolled >850 pediatric and adult patients with proteinuric glomerular diseases who have contributed to deep clinical, histologic, genetic, and molecular profiles linked to long-term outcomes. The NEPTUNE Knowledge Network, comprising combined, multiscalar data sets, captures each participant's molecular disease processes at the time of kidney biopsy. In this editorial, we describe the design and implementation of NEPTUNE Match, which bridges a basic science discovery pipeline with targeted clinical trials. Noninvasive biomarkers have been developed for real-time pathway analyses. A Molecular Nephrology Board reviews the pathway maps together with clinical, laboratory, and histopathologic data assembled for each patient to compile a Match report that estimates the fit between the specific molecular disease pathway(s) identified in an individual patient and proposed clinical trials. The NEPTUNE Match report is communicated using established protocols to the patient and the attending nephrologist for use in their selection of available clinical trials. NEPTUNE Match represents the first application of precision medicine in nephrology with the aim of developing targeted therapies and providing the right medication for each patient with primary glomerular disease., (Copyright © 2023 International Society of Nephrology. All rights reserved.)

Background: Hematuria is frequently present in podocytopathies, but its significance and prognostic value is not well described in these proteinuric kidney diseases. This study describes the prevalence and association between hematuria and kidney-related outcomes in these disorders., Methods: Hematuria was assessed at the initial urinalysis in participants with the following podocytopathies-membranous nephropathy, minimal change disease, and FSGS-in the Nephrotic Syndrome Study Network and Cure Glomerulonephropathy cohorts with >24 months of follow-up. Multivariable Cox proportional hazards models were fit for time to composite outcome (kidney failure or 40% decline in eGFR and eGFR <60 ml/min per 1.73 m 2 ) and proteinuria remission (urine protein-to-creatinine ratio [UPCR] <0.3 mg/mg)., Results: Among the 1516 adults and children in the study, 528 participants (35%) had FSGS, 499 (33%) had minimal change disease, and 489 (32%) had membranous nephropathy. Median (interquartile range) time from biopsy until the initial study urinalysis was 260 (49-750) days, and 498 participants (33%) were positive for hematuria. Participants with hematuria compared with those without were older (37 [16-55] versus 33 [12-55] years), more likely to have an underlying diagnosis of membranous nephropathy (44% versus 27%), had shorter time since biopsy (139 [27-477] versus 325 [89-878] days), and had higher UPCR (3.8 [1.4-8.0] versus 0.9 [0.1-3.1] g/g). After adjusting for diagnosis, age, sex, UPCR, eGFR, time since biopsy, and study cohort, hematuria was associated with a higher risk of reaching the composite outcome (hazard ratio, 1.31; 95% confidence interval, 1.04 to 1.65; P value, 0.02) and lower rate of reaching proteinuria remission (hazard ratio, 0.80; 95% confidence interval, 0.65 to 0.98; P value, 0.03)., Conclusions: Hematuria is prevalent among participants with the three podocytopathies and is significantly and independently associated with worse kidney-related outcomes, including both progressive loss of kidney function and remission of proteinuria., (Copyright © 2023 by the American Society of Nephrology.)

Competing Interests: Debbie Gipson received research funding through the University of Michigan from Reata, Travere, Novartis, Boehringer Ingelheim, and Goldfinch Bio and past consulting through the University of Michigan from Novartis, Vertex, and Genentech/Roche. Chia-shi Wang, Eloise Salmon, Rasheed Gbadegesin, Abhijit Naik, and Simone Sanna-Cherchi have no disclosures. Alessia Fornoni is one of the inventors on pending (PCT/US2019/032215; US 17/057,247; PCT/US2019/041730; PCT/US2013/036484; US 17/259,883; US17/259,883; JP501309/2021 and EU19834217.2; CN-201980060078.3; CA2,930,119; CA3,012,773; and CA2,852,904) or issued patents (US10,183,038 and US10,052,345) aimed at preventing and treating renal disease. She stands to gain royalties from their future commercialization. AF is vice president of L&F Health LLC and is a consultant for ZyVersa Therapeutics, Inc. ZyVersa Therapeutics, Inc., has licensed worldwide rights to develop and commercialize hydroxypropyl-beta-cyclodextrin for the treatment of kidney disease from L&F Research, which was partially funded by L&F Health LLC. She also holds equities in Renal 3 River Corporation. Matthias Kretzler has received research support on behalf of the University of Michigan from Boehringer Ingelheim, Novo Nordisk, Certa, Poxel, Astellas, and Janssen, has received research funding from NIH, JDRF, Chan Zuckerburg Initiative, amfAR, AstraZeneca, Boehringer Ingelheim, Elpidera, Gilead, Goldfinch Bio, Eli Lilly, Angion Biomedica, Certa, Novo Nordisk, Janssen, Chinook, RenalytixAI, Regeneron Pharmaceuticals, Travere Therapeutics, and Ionis Pharmaceuticals, is on the editorial boards for J Am Soc Nephrology, Kidney Int, and Kidney Dis, and is on an advisory board for NephCure Kidney International. Sandra Merscher is an inventor on pending and issued patents aimed to diagnose or treat proteinuric renal diseases. She stands to gain royalties from their future commercialization. She holds equity interest in L&F Research and is a shareholder of ZyVersa Pharmaceuticals, Inc., who has licensed worldwide rights to develop and commercialize hydroxypropyl-beta-cyclodextrin for the treatment of kidney diseases from L&F Research. Paul Hoover, Kelley Kidwell, Moin Saleem, Leonard Riella, Lawrence Holzman, Annette Jackson, and Opeyemi Olabisi have no disclosures. Paolo Cravedi is a consultant for Chinook therapeutics, Repertoire Immune Medicines, and Calliditas Therapeutics. Benjamin Freedman is an inventor on a patent and patent applications related to human kidney organoid differentiation and modeling of FSGS in this system (e.g., “three-dimensional differentiation of epiblast spheroids into kidney tubular organoids modeling human micro-physiology, toxicology, and morphogenesis” [Japan, USA, and Australia], licensed to STEMCELL Technologies). He has ownership interest in Plurexa LLC. Hailey Desmond received research funding through the University of Michigan from Boehringer Ingelheim, Travere, Roche, Novartis, and Reata. Howard Trachtman is a consultant to Travere Therapeutics Inc., Walden, Boehringer Ingelheim (pending), Natera, Otsuka, and Aclipse. He is the board of the Kidney Health Initiative and the editorial board of Pediatric Nephrology and Kidney360.

Background: In single-center studies, both preterm birth and low birth weight (LBW) are associated with worse outcomes in childhood nephrotic syndrome. Using the Nephrotic Syndrome Study Network (NEPTUNE) observational cohort, we tested the hypothesis that in patients with nephrotic syndrome, hypertension, proteinuria status, and disease progression would be more prevalent and more severe in subjects with LBW and prematurity singly or in combination (LBW/prematurity)., Methods: Three hundred fifty-nine adults and children with focal segmental glomerulosclerosis (FSGS) or minimal change disease (MCD) and available birth history were included. Estimated glomerular filtration rate (eGFR) decline and remission status were primary outcomes, and secondary outcomes were kidney histopathology, kidney gene expression, and urinary biomarkers. Logistic regression was used to identify associations with LBW/prematurity and these outcomes., Results: We did not find an association between LBW/prematurity and remission of proteinuria. However, LBW/prematurity was associated with greater decline in eGFR. This decline in eGFR was partially explained by the association of LBW/prematurity with APOL1 high-risk alleles, but the association remained after adjustment. There were no differences in kidney histopathology or gene expression in the LBW/prematurity group compared to normal birth weight/term birth., Conclusion: LBW and premature babies who develop nephrotic syndrome have a more rapid decline in kidney function. We did not identify clinical or laboratory features that distinguished the groups. Additional studies in larger groups are needed to fully ascertain the effects of (LBW) and prematurity alone or in combination on kidney function in the setting of nephrotic syndrome., (© 2023. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Glomerular diseases (GDs) represent the third leading cause of end-stage kidney disease (ESKD) in the US Diabetes was excluded from the CureGN Study, an NIH/NIDDK-sponsored observational cohort study of four leading primary GDs: IgA nephropathy (IgAN), membranous nephropathy (MN), focal segmental glomerulosclerosis (FSGS), and minimal change disease (MCD). CureGN-Diabetes, an ancillary study to CureGN, seeks to understand how diabetes influences the diagnosis, treatment, and outcomes of GD. It is a multicenter, prospective cohort study, targeting an enrollment of 300 adults with prevalent type 1 or type 2 diabetes and MCD, FSGS, MN, or IgAN, with first kidney biopsy obtained within 5 years of enrollment in 80% (20% allowed if biopsy after 2010). CureGN and Transformative Research in DiabEtic NephropaThy (TRIDENT) provide comparator cohorts. Retrospective and prospective clinical data and patient-reported outcomes are obtained. Blood and urine specimens are collected at study visits annually. Kidney biopsy reports and digital images are obtained, and standardized pathologic evaluations performed. Light microscopy images are uploaded to the NIH pathology repository. Outcomes include relapse and remission rates, changes in proteinuria and estimated glomerular filtration rate, infections, cardiovascular events, malignancy, ESKD, and death. Multiple analytical approaches will be used leveraging the baseline and longitudinal data to compare disease presentation and progression across subgroups of interest. With 300 patients and an average of 3 years of follow-up, the study has 80% power to detect a HR of 1.4-1.8 for time to complete remission of proteinuria, a rate ratio for hospitalizations of 1.18-1.56 and difference in eGFR slope of 6.0-8.6 mL/min/year between two groups of 300 participants each. CureGN-Diabetes will enhance our understanding of diabetes as a modifying factor of the pathology and outcomes of GDs and support studies to identify disease mechanisms and improve patient outcomes in this understudied patient population., Competing Interests: None of the authors have a COI related to this study. A.K.M. has received research support from Alexion, Bayer, Boehringer-Ingelheim, Calliditas, Duke Clinical Research Institute, and Pfizer; consulting fees from Bayer; and royalties from UpToDate. L.H.M. receives research support from Boehringer-Ingelheim and Travere Therapeutics; consulting fees from Reata Pharmaceuticals, Chinook Therapeutics, Travere Therapeutics, and Calliditas Therapeutics., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Introduction: Edema is a common manifestation of proteinuric kidney diseases, but there is no consensus approach for reliably evaluating edema. The objective of this study was to develop an edema clinician-reported outcome measure for use in patients with nephrotic syndrome., Methods: A literature review was conducted to assess existing clinician-rated measures of edema. Clinical experts were recruited from internal medicine, nephrology, and pediatric nephrology practices to participate in concept elicitation using semi-structured interviews and cognitive debriefing. Qualitative analysis methods were used to collate expert input and inform measurement development. In addition, training and assessment modules were developed using an iterative process that also utilized expert input and cognitive debriefing to ensure interrater reliability., Results: While several clinician-rated measures of edema have been proposed, our literature review did not identify any studies to support the reliability or validity of these measures. Fourteen clinician experts participated in the concept elicitation interviews, and twelve participated in cognitive debriefing. A clinician-reported outcome measure for edema was developed. The measure assesses edema severity in multiple individual body parts. An online training module and assessment tool were generated and refined using additional clinician input and investigative team expertise., Conclusion: The Edema ClinRO (V1) measure is developed specifically to measure edema in nephrotic syndrome. The tool assesses edema across multiple body parts, and it includes a training module to ensure standardized administration across raters. Future examination of this measure is ongoing to establish its reliability and validity., Competing Interests: Joshua Thurman receives royalties from Alexion Pharmaceuticals, Inc. He is a consultant for, will receive royalty income from, and holds stock in Q32 Bio Inc. He is also on the data review team for Goldfinch Bio. Michelle O’Shaughnessy is a consultant for Chinook Pharmaceuticals. Noelle Carlozzi, through the University of Michigan, received research funding for the design and conduct of this study. Laura Mariani, through the University of Michigan, has received research funding from the NIH, DOD, Nephcure Kidney International, and Boehringer Ingelheim unrelated to this work. She also receives personal consulting fees from Reata Pharmaceuticals, Calliditas Therapeutics, and Travere Therapeutics. Howard Trachtman is a consultant to Travere, Goldfinch Bio, Roche, and Walden and receives research funding from the NIH, DOD, and Natera. He is also Chair of DMC for pediatric studies conducted by Otsuka and is on the editorial board of Scientific Reports, Glomerular Diseases, Pediatric Nephrology, and Kidney360. Debbie Gipson, through the University of Michigan, received research funding for the design and conduct of this study from Goldfinch Bio and, through the University of Michigan, receives funding for research or consulting from Goldfinch Bio, Genentech, Roche, Boehringer Ingelheim, Travere, AstraZeneca, Novartis, Pfizer, Vertex, Reata, NIH, CDC, and FDA. Youssef Farag is a past employee of Goldfinch Bio. Liron Walsh is a past employee of Goldfinch Bio. All other authors report no conflicts of interest., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Rationale & Objective: Adolescent- and adult-onset minimal change disease (MCD) may have a clinical course distinct from childhood-onset disease. We characterized the course of children and adults with MCD in the Cure Glomerulonephropathy Network (CureGN) and assessed predictors of rituximab response., Study Design: Prospective, multicenter, observational study., Study Participants: CureGN participants with proven MCD on biopsy., Exposure: Age at disease onset, initiation of renin-angiotensin-aldosterone system (RAAS) blockade, and immunosuppression including rituximab during the study period., Outcome: Relapse and remission, change in estimated glomerular filtration rate (eGFR), and kidney failure., Analytical Approach: Remission and relapse probabilities were estimated using Kaplan-Meier curves and gap time recurrent event models. Linear regression models were used for the outcome of change in eGFR. Cox proportional hazards models were used to estimate the association between rituximab administration and remission., Results: The study included 304 childhood- (≤12 years old), 49 adolescent- (13-17 years old), and 201 adult- (≥18 years) onset participants with 2.7-3.2 years of follow-up after enrollment. Children had a longer time to biopsy (238 vs 23 and 36 days in adolescent- and adult-onset participants, respectively; P<0.001) and were more likely to have received therapy before biopsy. Children were more likely to be treated with immunosuppression but not RAAS blockade. The rate of relapse was higher in childhood- versus adult-onset participants (HR, 1.69 [95% CI, 1.29-2.21]). The probability of remission was also higher in childhood-onset disease (HR, 1.33 [95%CI, 1.02-1.72]). In all groups eGFR loss was minimal. Children were more likely to remit after rituximab than those with adolescent- or adult-onset disease (adjusted HR, 2.1; P=0.003). Across all groups, glucocorticoid sensitivity was associated with a greater likelihood of achieving complete remission after rituximab (adjusted HR, 2.62; P=0.002)., Limitations: CureGN was limited to biopsy-proven disease. Comparisons of childhood to nonchildhood cases of MCD may be subject to selection bias, given that childhood cases who undergo a biopsy may be limited to patients who are least responsive to initial therapy., Conclusions: Among patients with MCD who underwent kidney biopsy, there were differences in the course (relapse and remission) of childhood-onset compared with adolescent- and adult-onset disease, as well as rituximab response., Plain-Language Summary: Minimal change disease is a biopsy diagnosis for nephrotic syndrome. It is diagnosed in childhood, adolescence, or adulthood. Patients and clinicians often have questions about what to expect in the disease course and how to plan therapies. We analyzed a group of patients followed longitudinally as part of the Cure Glomerulonephropathy Network (CureGN) and describe the differences in disease (relapse and remission) based on the age of onset. We also analyzed rituximab response. We found that those with childhood-onset disease had a higher rate of relapse but also have a higher probability of reaching remission when compared with adolescent- or adult-onset disease. Children and all steroid-responsive patients are more likely to achieve remission after rituximab., (Copyright © 2023 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Persons with toxic gain-of-function variants in the gene encoding apolipoprotein L1 ( APOL1 ) are at greater risk for the development of rapidly progressive, proteinuric nephropathy. Despite the known genetic cause, therapies targeting proteinuric kidney disease in persons with two APOL1 variants (G1 or G2) are lacking., Methods: We used tetracycline-inducible APOL1 human embryonic kidney (HEK293) cells to assess the ability of a small-molecule compound, inaxaplin, to inhibit APOL1 channel function. An APOL1 G2-homologous transgenic mouse model of proteinuric kidney disease was used to assess inaxaplin treatment for proteinuria. We then conducted a single-group, open-label, phase 2a clinical study in which inaxaplin was administered to participants who had two APOL1 variants, biopsy-proven focal segmental glomerulosclerosis, and proteinuria (urinary protein-to-creatinine ratio of ≥0.7 to <10 [with protein and creatinine both measured in grams] and an estimated glomerular filtration rate of ≥27 ml per minute per 1.73 m 2 of body-surface area). Participants received inaxaplin daily for 13 weeks (15 mg for 2 weeks and 45 mg for 11 weeks) along with standard care. The primary outcome was the percent change from the baseline urinary protein-to-creatinine ratio at week 13 in participants who had at least 80% adherence to inaxaplin therapy. Safety was also assessed., Results: In preclinical studies, inaxaplin selectively inhibited APOL1 channel function in vitro and reduced proteinuria in the mouse model. Sixteen participants were enrolled in the phase 2a study. Among the 13 participants who were treated with inaxaplin and met the adherence threshold, the mean change from the baseline urinary protein-to-creatinine ratio at week 13 was -47.6% (95% confidence interval, -60.0 to -31.3). In an analysis that included all the participants regardless of adherence to inaxaplin therapy, reductions similar to those in the primary analysis were observed in all but 1 participant. Adverse events were mild or moderate in severity; none led to study discontinuation., Conclusions: Targeted inhibition of APOL1 channel function with inaxaplin reduced proteinuria in participants with two APOL1 variants and focal segmental glomerulosclerosis. (Funded by Vertex Pharmaceuticals; VX19-147-101 ClinicalTrials.gov number, NCT04340362.)., (Copyright © 2023 Massachusetts Medical Society.)

The diagnosis of nephrotic syndrome relies on clinical presentation and descriptive patterns of injury on kidney biopsies, but not specific to underlying pathobiology. Consequently, there are variable rates of progression and response to therapy within diagnoses. Here, an unbiased transcriptomic-driven approach was used to identify molecular pathways which are shared by subgroups of patients with either minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS). Kidney tissue transcriptomic profile-based clustering identified three patient subgroups with shared molecular signatures across independent, North American, European, and African cohorts. One subgroup had significantly greater disease progression (Hazard Ratio 5.2) which persisted after adjusting for diagnosis and clinical measures (Hazard Ratio 3.8). Inclusion in this subgroup was retained even when clustering was limited to those with less than 25% interstitial fibrosis. The molecular profile of this subgroup was largely consistent with tumor necrosis factor (TNF) pathway activation. Two TNF pathway urine markers were identified, tissue inhibitor of metalloproteinases-1 (TIMP-1) and monocyte chemoattractant protein-1 (MCP-1), that could be used to predict an individual's TNF pathway activation score. Kidney organoids and single-nucleus RNA-sequencing of participant kidney biopsies, validated TNF-dependent increases in pathway activation score, transcript and protein levels of TIMP-1 and MCP-1, in resident kidney cells. Thus, molecular profiling identified a subgroup of patients with either MCD or FSGS who shared kidney TNF pathway activation and poor outcomes. A clinical trial testing targeted therapies in patients selected using urinary markers of TNF pathway activation is ongoing., (Copyright © 2022 International Society of Nephrology. All rights reserved.)

Idiopathic nephrotic syndrome is the most frequent pediatric glomerular disease, affecting from 1.15 to 16.9 per 100,000 children per year globally. It is characterized by massive proteinuria, hypoalbuminemia, and/or concomitant edema. Approximately 85-90% of patients attain complete remission of proteinuria within 4-6 weeks of treatment with glucocorticoids, and therefore, have steroid-sensitive nephrotic syndrome (SSNS). Among those patients who are steroid sensitive, 70-80% will have at least one relapse during follow-up, and up to 50% of these patients will experience frequent relapses or become dependent on glucocorticoids to maintain remission. The dose and duration of steroid treatment to prolong time between relapses remains a subject of much debate, and patients continue to experience a high prevalence of steroid-related morbidity. Various steroid-sparing immunosuppressive drugs have been used in clinical practice; however, there is marked practice variation in the selection of these drugs and timing of their introduction during the course of the disease. Therefore, international evidence-based clinical practice recommendations (CPRs) are needed to guide clinical practice and reduce practice variation. The International Pediatric Nephrology Association (IPNA) convened a team of experts including pediatric nephrologists, an adult nephrologist, and a patient representative to develop comprehensive CPRs on the diagnosis and management of SSNS in children. After performing a systematic literature review on 12 clinically relevant PICO (Patient or Population covered, Intervention, Comparator, Outcome) questions, recommendations were formulated and formally graded at several virtual consensus meetings. New definitions for treatment outcomes to help guide change of therapy and recommendations for important research questions are given., (© 2022. The Author(s).)

Background: Children with chronic kidney disease (CKD) generally have worse educational and psychosocial outcomes compared with their healthy peers. This can impair their ability to manage their treatment, which in turn can have long-term health consequences through to adulthood. We attempted to capture the experiences of children with CKD and to describe the perspectives of their parents and caregivers on access to educational and psychosocial support., Methods: Children with CKD (n = 34) and their caregivers (n = 62) were sampled via focus groups from pediatric hospitals in Australia, Canada, and the USA. Sixteen focus groups were convened and the transcripts were analyzed thematically., Results: We identified four themes: disruption to self-esteem and identity (emotional turmoil of adolescence, wrestling with the sick self, powerlessness to alleviate child's suffering, balancing normality and protection); disadvantaged by lack of empathy and acceptance (alienated by ignorance, bearing the burden alone); a hidden and inaccessible support system (excluded from formal psychological support, falling behind due to being denied special considerations); and building resilience (finding partners in the journey, moving towards acceptance of the illness, re-establishing childhood)., Conclusions: Children with CKD and their caregivers encountered many barriers in accessing psychosocial and educational support and felt extremely disempowered and isolated as a consequence. Improved availability and access to psychosocial and educational interventions are needed to improve the wellbeing and educational advancement of children with CKD. 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.)

Artificial intelligence is playing an increasingly important role in many fields of clinical care to assist health care providers in patient management. In adult-focused nephrology, artificial intelligence is beginning to be used to improve clinical care, hemodialysis prescriptions, and follow-up of transplant recipients. This article provides an overview of medical artificial intelligence applications relevant to pediatric nephrology. We describe the core concepts of artificial intelligence and machine learning and cover the basics of neural networks and deep learning. We also discuss some examples for clinical applications of artificial intelligence in pediatric nephrology, including neonatal kidney function, early recognition of acute kidney injury, renally cleared drug dosing, intrapatient variability, urinary tract infection workup in infancy, and longitudinal disease progression. Furthermore, we consider the future of artificial intelligence in clinical pediatric nephrology and its potential impact on medical practice and address the ethical issues artificial intelligence raises in terms of clinical decision-making, health care provider-patient relationship, patient privacy, and data collection. This article also represents a call for action involving those of us striving to provide optimal services for children, adolescents, and young adults with chronic conditions., (Copyright © 2022 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Research on kidney diseases is being transformed by the rapid expansion and innovations in omics technologies. The analysis, integration, and interpretation of big data, however, have been an impediment to the growing interest in applying these technologies to understand kidney function and failure. Targeting this urgent need, the University of Michigan O'Brien Kidney Translational Core Center (MKTC) and its Administrative Core established the Applied Systems Biology Core. The Core provides need-based support for the global kidney community centered on enabling incorporation of systems biology approaches by creating web-based, user-friendly analytic and visualization tools, like Nephroseq and Nephrocell, guiding with experimental design, and processing, analysis, and integration of large data sets. The enrichment core supports systems biology education and dissemination through workshops, seminars, and individualized training sessions. Meanwhile, the Pilot and Feasibility Program of the MKTC provides pilot funding to both early-career and established investigators new to the field, to integrate a systems biology approach into their research projects. The relevance and value of the portfolio of training and services offered by MKTC are reflected in the expanding community of young investigators, collaborators, and users accessing resources and engaging in systems biology-based kidney research, thereby motivating MKTC to persevere in its mission to serve the kidney research community by enabling access to state-of-the-art data sets, tools, technologies, expertise, and learning opportunities for transformative basic, translational, and clinical studies that will usher in solutions to improve the lives of people impacted by kidney disease.

Importance: Focal segmental glomerulosclerosis (FSGS) is a common cause of end-stage kidney disease (ESKD) across the lifespan. While 10% to 15% of children and 3% of adults who develop ESKD have FSGS, it remains uncertain whether the natural history differs in pediatric vs adult patients, and this uncertainty contributes to the exclusion of children and adolescents in clinical trials., Objective: To examine whether there are differences in the kidney health outcomes among children, adolescents, and adults with FSGS., Design, Setting, and Participants: This cohort study used pooled and parallel analyses, completed July 5, 2022, from 3 complimentary data sources: (1) Nephrotic Syndrome Rare Disease Clinical Research Network (NEPTUNE); (2) FSGS clinical trial (FSGS-CT); and (3) Kidney Research Network (KRN). NEPTUNE is a multicenter US/Canada cohort study; FSGS-CT is a multicenter US/Canada clinical trial; and KRN is a multicenter US electronic health record-based registry from academic and community nephrology practices. NEPTUNE included 166 patients with incident FSGS enrolled at first kidney biopsy; FSGS-CT included 132 patients with steroid-resistant FSGS randomized to cyclosporine vs dexamethasone with mycophenolate; and KRN included 184 patients with prevalent FSGS. Data were collected from November 2004 to October 2019 and analyzed from October 2020 to July 2022., Exposures: Age: children (age <13 years) vs adolescents (13-17 years) vs adults (≥18 years). Covariates of interest included sex, disease duration, APOL1 genotype, urine protein-to-creatinine ratio, estimated glomerular filtration rate (eGFR), edema, serum albumin, and immunosuppressive therapy., Main Outcomes and Measures: ESKD, composite outcome of ESKD or 40% decline in eGFR, and complete and/or partial remission of proteinuria., Results: The study included 127 (26%) children, 102 (21%) adolescents, and 253 (52%) adults, including 215 (45%) female participants and 138 (29%) who identified as Black, 98 (20%) who identified as Hispanic, and 275 (57%) who identified as White. Overall, the median time to ESKD was 11.9 years (IQR, 5.2-19.1 years). There was no difference in ESKD risk among children vs adults (hazard ratio [HR], 0.67; 95% CI, 0.43-1.03) or adolescents vs adults (HR, 0.85; 95% CI, 0.52-1.36). The median time to the composite end point was 5.7 years (IQR 1.6-15.2 years), with hazard ratio estimates for children vs adults of 1.12 (95% CI, 0.83-1.52) and adolescents vs adults of 1.06 (95% CI, 0.75-1.50)., Conclusions and Relevance: In this study, the association of FSGS with kidney survival and functional outcomes was comparable at all ages.

Rationale & Objective: Clinical decision-making priorities may differ among children, their parents, and their clinicians. This study describes clinicians' perspectives on shared decision making in pediatric chronic kidney disease (CKD) and identifies opportunities to improve shared decision making and care for children with CKD and their families., Study Design: Semistructured interviews., Setting & Participants: Fifty clinicians participated, including pediatric nephrologists, nurses, social workers, surgeons, dietitians, and psychologists involved in providing care to children with CKD. They worked at 18 hospitals and 4 university research departments across 11 countries (United States of America, Canada, Australia, People's Republic of China, United Kingdom, Germany, France, Italy, Lithuania, New Zealand, and Singapore)., Analytical Approach: Interview transcripts were analyzed thematically., Results: We identified 4 themes: (1) striving to blend priorities (minimizing treatment burden, emphasizing clinical long-term risks, achieving common goals), (2) focusing on medical responsibilities (carrying decisional burden and pressure of expectations, working within system constraints, ensuring safety is foremost concern), (3) collaborating to achieve better long-term outcomes (individualizing care, creating partnerships, encouraging ownership and participation in shared decision making, sensitive to parental distress), and (4) forming cumulative knowledge (balancing reassurance and realistic expectations, building understanding around treatment, harnessing motivation for long-term goals)., Limitations: Most clinicians were from high-income countries, so the transferability of the findings to other settings is uncertain., Conclusions: Clinicians reported striving to minimize treatment burden and working with children and their families to manage their expectations and support their decision making. However, they are challenged with system constraints and sometimes felt the pressure of being responsible for the child's long-term outcomes. Further studies are needed to test whether support for shared decision making would promote strategies to establish and improve the quality of care for children with CKD., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Pediatric patients with nephrotic syndrome take medications long-term with significant toxicity and complex regimens, yet data on medication adherence are limited., Methods: In a multicenter observational study of patients with nephrotic syndrome, NEPTUNE (NCT01209000), we surveyed caregivers of patients <19 years old and adolescent patients on medication adherence during longitudinal follow-up beginning in June 2015. Data extraction was in October 2020. We described the proportion of nonadherent patients at first survey. Participant social and economic factors, condition-related factors, therapy-related factors, and patient-related factors were examined for relationships with nonadherence by generalized linear mixed models using the longitudinal data. In exploratory fashion, we assessed the relationship between adherence and subsequent steroid response classification by binary logistic regression and adherence with healthcare utilization by Poisson regression., Results: A total of 225 participants completed a median of 3 surveys during follow-up (IQR, 2-5), with a total of 743 surveys. Overall, 80 (36%) reported nonadherence with medications. In adjusted analysis, older age (per 1 year; OR 1.08; 95% CI, 1.03 1.12), lower maternal educational level (≥ high school vs. < high school; OR 0.47; 95% CI 0.25 to 0.89), and increased parent and self-identification of medications barriers (per 1 point; OR 1.57; 95% CI, 1.15-2.15) were significantly associated with nonadherence. No relationship between nonadherence and subsequent frequency of healthcare utilization was observed. A trend toward increased subsequent steroid resistance classification was seen with nonadherence, though not statistically significant., Conclusions: Medication nonadherence is common in pediatric nephrotic syndrome. Investigations into the use of surveys in the clinic setting to identify at-risk patients and ways to support families over time are needed. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2021. IPNA.)

Objective: To compare specific attention functions for school-age children with chronic kidney disease (CKD) to those of a typically developing control group., Methods: A cross-sectional study examined attention dimensions for children and adolescents with CKD ( n = 30) in comparison to a typically developing control group ( n = 41). The CKD group consisted of those receiving maintenance dialysis ( n = 15) and those with mild/moderate CKD treated conservatively ( n = 15). Measures aligning with Mirsky's conceptual multidimensional model of attention were selected to compare groups across five dimensions of attention: Focus/Execute, Sustain, Stability, Shift, and Encode., Results: Significant group differences were revealed, with the CKD group performing worse than controls on the Focus/Execute, Sustain, and Encode dimensions. The CKD group also had a larger proportion of children with scores one standard deviation or more below the mean on the Shift and Encode domains, suggesting an at-risk level of functioning in these dimensions. Secondary analyses showed disease severity to be correlated with worse attention functions for children with CKD., Conclusion: Children with CKD may be vulnerable to subtle, specific deficits in numerous attention dimensions relative to their typically developing peers, particularly for those with more severe disease., Competing Interests: The 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 © 2022 Duquette, Gipson and Hooper.)

Background: More than 50% of children with chronic kidney disease (CKD) have uncontrolled hypertension, increasing their long-term risk of cardiovascular disease and progression to kidney failure. Children receiving medications or dialysis may also experience acute blood pressure fluctuations accompanied by debilitating symptoms. We aimed to describe the perspectives of children with CKD and their parental caregivers on blood pressure to inform patient-centered care., Methods: Secondary thematic analysis was conducted on qualitative data from the Standardized Outcomes in Nephrology-Children and Adolescents initiative, encompassing 16 focus groups, an international Delphi survey and two consensus workshops. We analyzed responses from children with CKD (ages 8-21 years) and caregivers (of children ages 0-21 years) pertaining to blood pressure., Results: Overall, 120 patients and 250 caregivers from 22 countries participated. We identified five themes: invisibility and normalization (reassured by apparent normotension, absence of symptoms and expected links with CKD), confused by ambiguity (hypertension indistinguishable from cardiovascular disease, questioning the need for prophylactic intervention, frustrated by inconsistent messages and struggling with technical skills in measurement), enabling monitoring and maintaining health (gaging well-being and preventing vascular complications), debilitating and constraining daily living (provoking anxiety and agitation, helpless and powerless and limiting life activities) and burden of medications (overwhelmed by the quantity of tablets and distress from unexpected side effects)., Conclusions: For children with CKD and their caregivers, blood pressure was an important heath indicator, but uncertainty around its implications and treatment hampered management. Providing educational resources to track blood pressure and minimizing symptoms and treatment burden may improve outcomes in children with CKD., (© The Author(s) 2021. Published by Oxford University Press on behalf of ERA-EDTA.)

Introduction: Minimal change disease in childhood can follow a frequently relapsing or steroid-dependent course in up to 40% of cases. Second-line immunosuppressive medications that are used to manage these patients are associated with significant adverse effects. There is a need for safer alternative treatments for difficult-to-treat nephrotic syndrome. Therefore, we conducted an open-label feasibility study to assess the safety and efficacy of a gluten-free diet as treatment for pediatric patients with difficult-to-treat nephrotic syndrome. As a second aim, we sought to determine if the plasma zonulin concentration can identify those who are more likely to respond to this intervention., Methods: Seventeen patients were placed on a gluten-free diet for 6 months. A positive response was defined as a 50% reduction in the relapse rate compared to the preceding 6 months or the ability to discontinue 1 immunosuppressive drug., Results: Five (29%) participants had a positive response to the dietary intervention. The gluten-free diet was well tolerated with no clinical or laboratory adverse events. Plasma zonulin concentration was elevated in patients who failed to benefit from the gluten-free diet., Discussion/conclusion: A gluten-free diet may be a useful adjunctive intervention for patients with difficult-to-treat nephrotic syndrome that can be implemented prior to resorting to second-line immunosuppressive therapy. Development of the plasma zonulin level as a biomarker to predict efficacy would facilitate rational use of a gluten-free diet in the management of nephrotic syndrome., Competing Interests: None of the authors have a conflict of interest relevant to this study., (Copyright © 2022 by The Author(s). Published by S. Karger AG, Basel.)

Background: Long-term outcomes after multiple courses of rituximab among children with frequently relapsing, steroid-dependent nephrotic syndrome (FRSDNS) are unknown., Methods: A retrospective cohort study at 16 pediatric nephrology centers from ten countries in Asia, Europe, and North America included children with FRSDNS who received two or more courses of rituximab. Primary outcomes were relapse-free survival and adverse events., Results: A total of 346 children (age, 9.8 years; IQR, 6.6-13.5 years; 73% boys) received 1149 courses of rituximab. A total of 145, 83, 50, 28, 22, and 18 children received two, three, four, five, six, and seven or more courses, respectively. Median (IQR) follow-up was 5.9 (4.3-7.7) years. Relapse-free survival differed by treatment courses (clustered log-rank test P <0.001). Compared with the first course (10.0 months; 95% CI, 9.0 to 10.7 months), relapse-free period and relapse risk progressively improved after subsequent courses (12.0-16.0 months; HR adj , 0.03-0.13; 95% CI, 0.01 to 0.18; P <0.001). The duration of B-cell depletion remained similar with repeated treatments (6.1 months; 95% CI, 6.0 to 6.3 months). Adverse events were mostly mild; the most common adverse events were hypogammaglobulinemia (50.9%), infection (4.5%), and neutropenia (3.7%). Side effects did not increase with more treatment courses nor a higher cumulative dose. Only 78 of the 353 episodes of hypogammaglobulinemia were clinically significant. Younger age at presentation (2.8 versus 3.3 years; P =0.05), age at first rituximab treatment (8.0 versus 10.0 years; P= 0.01), and history of steroid resistance (28% versus 18%; P =0.01) were associated with significant hypogammaglobulinemia. All 53 infective episodes resolved, except for one patient with hepatitis B infection and another with EBV infection. There were 42 episodes of neutropenia, associated with history of steroid resistance (30% versus 20%; P =0.04). Upon last follow-up, 332 children (96%) had normal kidney function., Conclusions: Children receiving repeated courses of rituximab for FRSDNS experience an improving clinical response. Side effects appear acceptable, but significant complications can occur. These findings support repeated rituximab use in FRSDNS., (Copyright © 2022 by the American Society of Nephrology.)

Background: Nephrotic syndrome (NS) is a rare kidney syndrome with high morbidity. Although a common contributor to the burden of chronic kidney disease, the direct and indirect costs of NS to patients and family caregivers are unrecognized. The objective was to characterize the direct and indirect costs of NS to patients., Methods: Adults with NS and family caregivers of children with NS were eligible to participate if they had a diagnosis of primary NS, had disease for at least 1 year, and had no other severe health conditions. Data-collection surveys were generated with input from the Kidney Research Network Patient Advisory Board, and surveys were mailed to the eligible participants. Participants were provided $50 for the return of completed surveys. Costs were defined as either direct out-of-pocket costs or indirect costs ( e.g. , time). Descriptive statistics, including percentage and median (interquartile range [IQR]) are reported., Results: Respondents included 28 adult patients and 17 caregivers of patients who were minors. Reported health insurance coverage included 35 (78%) with private insurance, 12 (27%) with public insurance, six (13%) with Children's Special Health Care Services, and one (2%) uninsured. Median annual direct costs were $3464 ($844-$5865) for adult patients and $1687 (IQR $1035-$4763) for caregivers. Of these costs, diet-associated costs contributed $1140 (IQR $600-$2400). The most substantial indirect cost was from the time spent planning/prepping meals (adults: 183 h/yr [IQR 114-331]; caregivers: 173 h/yr [IQR 84-205])., Conclusions: Adults and caregivers of children with NS face substantial disease-related direct and indirect costs beyond those covered by insurance. Following replication, the study will help health care providers, systems, and payers gain a better understanding of the financial and time burden incurred by those living with NS, consider barriers when treating patients, and develop supportive strategies., Competing Interests: D.S. Gipson reports consultancy between the University of Michigan and AstraZeneca, Boehringer-Ingelheim, Genentech, Goldfinch Bio, Roche, Travere, and Vertex (no individual consultancy agreements); research funding to the University of Michigan from BoehringerIngelheim, Goldfinch Bio, Novartis, Reata, and Travere; being a scientific advisor for or a member of AstraZeneca, Goldfinch Bio, and Vertex; and other interests/relationships with the Nephrotic Syndrome Patient Reported Outcome Consortium (public-private partnership, with Goldfinch Bio, GSK, Pfizer, and Zyversa; NephCure Kidney International). S. Massengill reports consultancy agreements with Guidepoint Network and being a scientific advisor for or a member of the Editorial Board of online Glomerular Disease Journal (Karger Publishers). All remaining authors have nothing to disclose., (Copyright © 2022 by the American Society of Nephrology.)

Outcomes relevant to treatment decision-making are inconsistently reported in trials involving glomerular disease. Here, we sought to establish a consensus-derived set of critically important outcomes designed to be reported in all future trials by using an online, international two-round Delphi survey in English. To develop this, patients with glomerular disease, caregivers and health professionals aged 18 years and older rated the importance of outcomes using a Likert scale and a Best-Worst scale. The absolute and relative importance was assessed and comments were analyzed thematically. Of 1198 participants who completed Round 1, 734 were patients/caregivers while 464 were health care professionals from 59 countries. Of 700 participants that completed Round 2, 412 were patients/caregivers and 288 were health care professionals. Need for dialysis or transplant, kidney function, death, cardiovascular disease, remission-relapse and life participation were the most important outcomes to patients/caregivers and health professionals. Patients/caregivers rated patient-reported outcomes higher while health care professionals rated hospitalization, death and remission/relapse higher. Four themes explained the reasons for their priorities: confronting death and compounded suffering, focusing on specific targets in glomerular disease, preserving meaning in life, and fostering self-management. Thus, consistent reporting of these critically important outcomes in all trials involving glomerular disease is hoped to improve patient-centered decision-making., (Copyright © 2021 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

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: The G1 and G2 alleles of apolipoprotein L1 (APOL1) are common in the Black population and associated with increased risk of focal segmental glomerulosclerosis (FSGS). The molecular mechanisms linking APOL1 risk variants with FSGS are not clearly understood, and APOL1's natural absence in laboratory animals makes studying its pathobiology challenging., Methods: In a cohort of 90 Black patients with either FSGS or minimal change disease (MCD) enrolled in the Nephrotic Syndrome Study Network (58% pediatric onset), we used kidney biopsy traits as an intermediate outcome to help illuminate tissue-based consequences of APOL1 risk variants and expression. We tested associations between APOL1 risk alleles or glomerular APOL1 mRNA expression and 83 light- or electron-microscopy traits measuring structural and cellular kidney changes., Results: Under both recessive and dominant models in the FSGS patient subgroup (61%), APOL1 risk variants were significantly correlated (defined as FDR <0.1) with decreased global mesangial hypercellularity, decreased condensation of cytoskeleton, and increased tubular microcysts. No significant correlations were detected in MCD cohort. Independent of risk alleles, glomerular APOL1 expression in FSGS patients was not correlated with morphologic features., Conclusions: While APOL1-associated FSGS is associated with two risk alleles, both one and two risk alleles are associated with cellular/tissue changes in this study of FSGS patients. Our lack of discovery of a large group of tissue differences in FSGS and no significant difference in MCD may be due to the lack of power but also supports investigating whether machine learning methods may more sensitively detect APOL1-associated changes., (© 2021. IPNA.)

This cross-sectional study provides preliminary findings from one of the first functional brain imaging studies in children with chronic kidney disease (CKD). The sample included 21 children with CKD (ages, 14.4 ± 3.0 y) and 11 healthy controls (ages, 14.5 ± 3.4 y). Using functional magnetic resonance imaging during a visual-spatial working memory task, findings showed that the CKD group and healthy controls invoked similar brain regions for encoding and retrieval phases of the task, but significant group differences were noted in the activation patterns for both components of the task. For the encoding phase, the CKD group showed lower activation in the posterior cingulate, anterior cingulate, precuneus, and middle occipital gyrus than the control group, but more activation in the superior temporal gyrus, middle frontal gyrus, middle temporal gyrus, and the insula. For the retrieval phase, the CKD group showed underactivation for brain systems involving the posterior cingulate, medial frontal gyrus, occipital lobe, and middle temporal gyrus, and greater activation than the healthy controls in the postcentral gyrus. Few group differences were noted with respect to disease severity. These preliminary findings support evidence showing a neurologic basis to the cognitive difficulties evident in pediatric CKD, and lay the foundation for future studies to explore the neural underpinnings for neurocognitive (dys)function in this population., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: A critical unmet need exists for precision therapies for chronic kidney disease. GFB-887 is a podocyte-targeting, small molecule inhibitor of transient receptor potential canonical-5 (TRPC5) designed specifically to treat patients with glomerular kidney diseases characterized by an overactivation of the TRPC5-Rac1 pathway. In a first-in-human study, GFB-887 was found to be safe and well tolerated, had a pharmacokinetic (PK) profile allowing once-daily dosing, and dose dependently decreased urinary Rac1 in healthy adults., Methods: TRACTION-2 is a phase 2a, double-blind, placebo-controlled, multiple-ascending dose study of GFB-887 in patients with focal segmental glomerulosclerosis (FSGS), treatment-resistant minimal change disease (TR-MCD), or diabetic nephropathy (DN) (NCT04387448). Adult patients on stable renin-angiotensin system blockade and/or immunosuppression with persistent proteinuria will be randomized and dosed in 3 ascending dose levels to GFB-887 or placebo for 12 weeks. Cohorts may be expanded or biomarker-enriched depending upon results of an adaptive interim analysis., Results: The primary objective is to evaluate the effect of increasing doses of GFB-887 on proteinuria. Safety and tolerability, quality of life, pharmacokinetic/pharmacodynamic profiles, and the potential association of urinary Rac1 with efficacy will also be evaluated. The projected sample size has 80% power to detect a treatment difference in proteinuria of 54% (FSGS/TR-MCD) or 44% (DN) compared to placebo., Conclusion: TRACTION-2 will explore whether targeted blockade of the TRPC5-Rac1 pathway with GFB-887 is an efficacious and safe treatment strategy for patients with FSGS, TR-MCD, and DN and the potential value of urinary Rac1 as a predictive biomarker of treatment response., (© 2021 Published by Elsevier, Inc., on behalf of the International Society of Nephrology.)

Introduction: Patients with chronic health conditions, particularly chronic kidney disease, are at heightened risk for psychiatric disorders; yet, there are limited data on those with primary glomerular disease., Methods: This study included patients with glomerular disease enrolled in the kidney research network multisite patient registry. Registry data include encounter, diagnoses, medication, laboratory, and vital signs data extracted from participants' electronic health records. ICD-9/10 diagnosis codes were used to identify a subset of psychiatric disorders focused on anxiety, mood, and behavioral disorders. Time-varying Cox proportional hazard models were used to analyze time from the onset of kidney disease to diagnosis of psychiatric disorder. Adjusted models retained significant covariates from the full list of potential confounders, including age, sex, race, ethnicity, time-varying treatment, the estimated glomerular filtration rate, and proteinuria (urine protein-to-creatinine ratio [UPCR]). Analogous models examined diagnosis of psychiatric disorder as a predictor of time to end-stage kidney disease (ESKD)., Results: Data were available for 950 participants, with a median of 58 months of follow-up. 110 (12%) participants were diagnosed with psychiatric disorder during the follow-up. The estimated rate of psychiatric diagnosis after kidney disease was 14.7 cases per 1,000 person-years and was highest among those of adolescent age at the time of kidney disease diagnosis. Adjusted analyses found adolescent age (vs. adult, hazard ratio [HR] = 3.11, 95% confidence interval [CI] 1.87-5.17) and Asian race (vs. white, HR = 0.34, 95% CI 0.16-0.71) were associated with psychiatric diagnosis. A higher UPCR per 1 log unit (HR 1.13, 95% CI 1.01-1.27) and a higher total number of oral medications were associated with psychiatric disorder ( p < 0.001). Psychiatric diagnosis was also associated with progression to ESKD (HR = 2.45, 95% CI 1.53-3.92) in adjusted models., Discussion/conclusion: Psychiatric disorders were documented in approximately one-eighth of patients with glomerular disease and correlated with clinical disease characteristics such as age, race, proteinuria, and oral medication burden. These findings suggest mental health screening is warranted in patients of all ages with glomerular disease., Competing Interests: Though there are no conflicts of interest or disclosures related to these data, the authors would like to report the following financial relationships: J.P.T. has research funding through the University of Michigan (UM) with Retrophin Inc., Goldfinch Bio, Vertex Pharmaceuticals, and Pfizer Inc. D.S.G. has research funding through the UM with Retrophin Inc., Goldfinch Bio, Novartis, and Reata Pharmaceuticals, and consults through UM with Vertex and AstraZeneca. E.S.K. has research funding from Pfizer, has served as a one-time consultant for Mallinckrodt, and serves on the Board of NephCure Kidney International. S.F.M. serves on the Retrophin Advisory Board., (Copyright © 2021 by The Author(s) Published by S. Karger AG, Basel.)

Background and Objective: The use of electronic health record (EHR) data can facilitate efficient research and quality initiatives. The imprecision of ICD-10 codes for kidney diagnoses has been an obstacle to discrete data-defined diagnoses in the EHR. This manuscript describes the Kidney Research Network (KRN) registry and database that provide an example of a prospective, real-world data glomerular disease registry for research and quality initiatives., Methods: KRN is a multicenter collaboration of patients, physicians, and scientists across diverse health-care settings with a focus on improving treatment options and outcomes for patients with glomerular disease. The registry and data warehouse amasses retrospective and prospective data including EHR, active research study, completed clinical trials, patient reported outcomes, and other relevant data. Following consent, participating sites enter the patient into KRN and provide a physician-confirmed primary kidney diagnosis. Kidney biopsy reports are redacted and uploaded. Site programmers extract local EHR data including demographics, insurance type, zip code, diagnoses, encounters, laboratories, procedures, medications, dialysis/transplant status, vitals, and vital status monthly. Participating sites transform data to conform to a common data model prior to submitting to the Data Analysis and Coordinating Center (DACC). The DACC stores and reviews each site's EHR data for quality before loading into the KRN database., Results: As of January 2021, 1,192 patients have enrolled in the registry. The database has been utilized for research, clinical trial design, clinical trial end point validation, and supported quality initiatives. The data also support a dashboard allowing enrolling sites to assist with clinical trial enrollment and population health initiatives., Conclusion: A multicenter registry using EHR data, following physician- and biopsy-confirmed glomerular disease diagnosis, can be established and used effectively for research and quality initiatives. This design provides an example which may be readily replicated for other rare or common disease endeavors., Competing Interests: Though there are no conflicts of interest or disclosures related to these data, the authors would like to report the following financial relationships: S.F.M. serves on the Travere Advisory Board. E.S.K. has research funding from Pfizer, has served as a onetime consultant for Mallinckrodt, and serves on the Board of NephCure Kidney International. D.S.G. has research funding through the UM with Travere, Goldfinch Bio, Novartis, and Reata Pharmaceuticals and consults through UM with Vertex and AstraZeneca; the remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 by The Author(s) Published by S. Karger AG, Basel.)

Like many pediatric chronic health conditions, idiopathic childhood onset nephrotic syndrome (iCONS) and late effects of iCONS medical management may continue to impact the affected population in adulthood. Approximately 15% of adult survivors of steroid-sensitive iCONS continue to relapse. Long-term kidney health is associated with steroid response patterns as well as pathology findings of FSGS, tubulointerstitial fibrosis, tubular atrophy, and global glomerulosclerosis. Long-term cardiovascular disease burden is largely unknown in adult survivors, but risk factors starting in childhood, including hypertension, dyslipidemia, and obesity, are common in iCONS. Reproductive health concerns, including azo-/oligospermia and successful pregnancies, are largely related to prior exposure to cytotoxic therapies. Additional investigations are needed to complete the assessment and initiate the mitigation of the late effects of treatment-sensitive and treatment-resistant iCONS.

Introductions: Kidney injury molecule-1 (KIM-1) and periostin (POSTN) are proximal and distal tubule injury biomarkers. We tested whether baseline urine KIM-1/creatinine (uKIM-1/cr) and/or uPOSTN/cr correlated with disease severity or improved a remission prediction model., Methods: Baseline uKIM1/cr and uPOSTN/cr were measured on spot urine samples from immunosuppression-free patients enrolled in Nephrotic Syndrome Study Network until December 15, 2014. Urine protein/creatinine (UPCR) and albumin/creatinine (UACR) were measured at baseline, 4 months, and until last follow-up. Glomerular and tubulointerstitial (TI) expression arrays were analyzed from a baseline research renal biopsy core collected during a clinically indicated biopsy.Renal diagnoses were centrally confirmed, sections scanned, and measured morphometrically. Correlations between baseline uKIM-1/cr and uPOSTN/cr and UPCR, UACR, histopathologic features, glomerular and TI KIM-1 and POSTN expression levels, and renal outcomes were assessed., Results: Baseline uKIM-1/cr correlated with UPCR and UACR, and were associated with complete remission after adjustment for proteinuria, histopathologic diagnosis, and treatment. Baseline uKIM-1/cr also correlated with degree of foot process effacement and acute tubular injury. Glomerular and TI KIM-1 expression levels correlated with UPCR and UACR. Higher TI KIM-1 expression levels correlated with interstitial fibrosis, tubular atrophy, and global glomerulosclerosis, while glomerular KIM-1 expression correlated with time to remission. Findings for POSTN were of lesser statistical strength., Discussion/conclusion: Lower baseline uKIM-1/cr values were associated with more rapid time to complete remission after adjusting for proteinuria, histopathologic diagnosis, and treatment. Increased TI KIM-1 expression levels in proteinuric states were associated with chronic morphological injury; lower glomerular expression levels were associated with a greater potential for proteinuria reversibility., Competing Interests: Conflict of Interest Statement JT and DG have research funding through the University of Michigan with Complexa Inc., Retrophin Inc. and Goldfinch Bio (DG additionally has funding through the University of Michigan with Bristol-Meyers Squibb; JT through the University of Michigan with Vertex Pharmaceuticals and Pfizer Inc.).

Introduction: The number of medications could serve as a surrogate for burden of care at home and may affect health-related quality of life (HRQoL) in children with chronic kidney disease (CKD)., Methods: Using baseline data from the Chronic Kidney Disease in Children (CKiD) Study, we modeled HRQoL scores, self-reported by the child (if ≥ 8 years old) and/or caregiver (all children) on unique counts and administrations of CKD- and non-CKD-related medications, using multivariate linear regression. Heterogeneity of associations between HRQoL and medication burden by age group (≥ 8 vs. < 8 years old) were explored., Results: 734 participants median age 11 years, disease duration 8 years, median eGFR 53 mL/min/1.73 m 2 , 61% male, 22% African-American, 31% glomerular disease were prescribed median 3 unique CKD-related medications. Regarding HRQoL assessment, 201 children were < 8 years old and had only parent-proxy HRQoL score; 533 children ≥ 8 years of age had both child and parent-proxy scores. Overall, parents of children < 8 years old reported higher HRQoL scores than parents of older children: 84 vs. 76. However, in a unified multivariate regression model, HRQoL scores of children < 8 years showed greater decreases as the number of CKD-related medications increased compared to scores for children ≥ 8 years old., Conclusion: Average HRQoL scores reported by parents of younger CKD children were higher than those of older CKD children but decreased more with increased CKD medication counts than scores of older children. Considerations of HRQoL may be of particular importance for clinicians and caregivers when managing chronic disease comorbidities in younger children.

Rationale & Objective: Assessment of how patients feel and function is needed for clinical care and research for focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD). The objective of this study was to develop a patient-reported outcome assessment appropriate for use in children and adults with FSGS and MCD., Study Design: Qualitative study using semi-structured interviews., Setting & Participants: 48 semi-structured interviews with children aged 8 to 17 years (n = 11) and adults (n = 10) with FSGS and children aged 8 to 17 (n = 11) and adults (n = 16) with MCD recruited from 3 academic medical centers., Analytical Approach: Latent content analysis., Results: FSGS and MCD have a pervasive and comparable impact on physical, social, and mental health-related quality of life regardless of age or diagnosis. Physical symptoms of swelling, fatigue, and pain were articulated by most participants. Disease management was also a frequent topic of discussion; participants described their experiences with medication and associated side effects, as well as lifestyle changes made to manage their disease (ie, dietary changes and frequent medical appointments). These discussions often identified a profound impact on physical abilities and life participation. In many instances, participants described the negative impact these symptoms had on their mood and sense of self, with most participants reporting feelings of anxiety., Limitations: Participants were primarily non-Hispanic White and English speaking, which may limit generalizability., Conclusions: Our results suggest that there are commonalities to the FSGS-MCD patient experience of health-related quality of life that will enable the generation of a disease-specific FSGS-MCD patient-reported outcomes instrument for use in children and adults. The development of this tool is intended to facilitate better care and support clinical research for these individuals., (© 2021 The Authors.)

Rationale & Objective: The impact of chronic kidney disease (CKD) on inpatient health care use is unknown. This study aimed to describe the prevalence of pediatric CKD among children hospitalized in the United States and examine the association of CKD with hospital outcomes., Study Design: Cross-sectional national survey of pediatric discharges., Setting & Participants: Hospital discharges of children (aged>28 days to 19 years) with a chronic medical diagnosis included in the Healthcare Cost and Utilization Project Kids' Inpatient Database for 2006, 2009, 2012, and 2016., Predictor: Presence of primary or coexisting CKD as identified by diagnosis codes., Outcomes: Length of stay (LOS), cost, and mortality., Analytical Approach: Multivariable analysis using Poisson, gamma, and logistic regressions were performed for LOS, cost, and mortality, respectively., Results: A chronic medical condition was present in 6,524,745 estimated discharges during the study period and CKD was present among 3.9% of discharges (96.1% without CKD). Those with CKD had a longer LOS (median of 2.8 [IQR, 1.4-6.0] days compared with 1.8 [IQR, 1.0-4.4] days for those without a CKD diagnosis; P<0.001). Median cost was higher in the CKD group compared with the group without CKD, at $8,755 (IQR, $4,563-18,345) and $5,016 (IQR, $2,860-10,109) per hospitalization, respectively (P<0.001). Presence of CKD was associated with a longer LOS (29.9% [95% CI, 27.2%-32.6%] longer than those without CKD), higher cost (61.3% [95% CI, 57.4%-65.4%] greater than those without CKD), and higher risk for mortality (OR, 1.51 [95% CI, 1.40-1.63])., Limitations: Lack of access to and adjustment for confounders including patient readmission and laboratory data., Conclusions: Pediatric CKD was associated with longer LOS, higher costs, and higher risk for mortality compared with hospitalizations with other chronic illnesses. Further studies are needed to better understand the health care needs and delivery of care to hospitalized children with CKD., (Copyright © 2020 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: High data quality is of crucial importance to the integrity of research projects. In the conduct of multi-center observational cohort studies with increasing types and quantities of data, maintaining data quality is challenging, with few published guidelines., Methods: The Cure Glomerulonephropathy (CureGN) Network has established numerous quality control procedures to manage the 70 participating sites in the United States, Canada, and Europe. This effort is supported and guided by the activities of several committees, including Data Quality, Recruitment and Retention, and Central Review, that work in tandem with the Data Coordinating Center to monitor the study. We have implemented coordinator training and feedback channels, data queries of questionable or missing data, and developed performance metrics for recruitment, retention, visit completion, data entry, recording of patient-reported outcomes, collection, shipping and accessing of biological samples and pathology materials, and processing, cataloging and accessing genetic data and materials., Results: We describe the development of data queries and site Report Cards, and their use in monitoring and encouraging excellence in site performance. We demonstrate improvements in data quality and completeness over 4 years after implementing these activities. We describe quality initiatives addressing specific challenges in collecting and cataloging whole slide images and other kidney pathology data, and novel methods of data quality assessment., Conclusions: This paper reports the CureGN experience in optimizing data quality and underscores the importance of general and study-specific data quality initiatives to maintain excellence in the research measures of a multi-center observational study., Competing Interests: HT is a consultant to Otsuka and Chemocentryx (Data Monitoring Committees) and receives support from Travere Therapeutic and Goldfinch BioPharma Inc. through separate grants to 10.13039/100006732New York University. In addition, he has received research support from Natera Inc. LAG receives research support from 10.13039/100011022Vertex Pharmaceuticals and Reata Pharmaceuticals. SEW has a consulting agreement with Bristol-Myers Squibb. The remaining authors declare no perceived or actual COIs., (© 2021 Published by Elsevier Inc.)

Background: Children with nephrotic syndrome (NS) are at high risk for vaccine-preventable infections due to the immunological effects from the disease and concurrent treatment with immunosuppressive medications. Immunizations in these patients may be deferred due to their immunosuppressive treatment which may increase the risk for vaccine-preventable infections. Immunization practices in children with NS continue to vary among pediatric nephrologists. This raises the question of whether children with NS are receiving the recommended vaccinations at appropriate times. Therefore, it is critical to understand the practices and patient education provided by physicians to patients on the topic of vaccinations. Methods: After informed consent, parents/guardians of 153 pediatric patients (<18 years old) diagnosed with NS from 2005 to 2018 and 50 pediatric nephrologists from 11 participating centers completed anonymous surveys to evaluate immunization practices among pediatric nephrologists, assess the vaccine education provided to families of children with NS, assess the parental knowledge of immunization recommendations, and assess predictors of polysaccharide pneumococcal vaccine adherence. The Advisory Committee on Immunization Practices (ACIP) Immunization 2019 Guideline for those with altered immunocompetence was used to determine accuracy of vaccine knowledge and practices. Results: Forty-four percent of providers self-reported adherence to the ACIP guidelines for inactive vaccines and 22% to the guidelines for live vaccines. Thirty-two percent of parents/guardians reported knowledge that aligned with the ACIP guidelines for inactive vaccines and 1% for live vaccines. Subjects residing in the Midwest and provider recommendations for vaccines were positive predictors of vaccine adherence ( p < 0.001 and p 0.02, respectively). Conclusions: Vaccine recommendation by medical providers is paramount in vaccine adherence among pediatric patients with NS. This study identifies potential educational opportunities for medical subspecialty providers and family caregivers about immunization recommendations for immunosuppressed patients., Competing Interests: The 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 Tran, Selewski, Oh, Troost, Massengill, Al-Akash, Mahesh, Amin, Ashoor, Chanchlani, Kallash, Woroniecki and Gipson.)

Rationale & Objective: Remission of proteinuria has been shown to be associated with lower rates of kidney disease progression among people with focal segmental glomerulosclerosis (FSGS). The goal of this study was to evaluate whether reductions in proteinuria after treatment are associated with greater kidney survival., Study Design: Cohort analysis of clinical trial participants., Setting & Participants: Patients with steroid-resistant FSGS enrolled in a randomized treatment trial that compared cyclosporine with mycophenolate mofetil plus dexamethasone., Predictors: Reduction in proteinuria measured during 26 weeks after initiating treatment., Outcomes: Repeated assessments of estimated glomerular filtration rate (eGFR) and time to a composite outcome of kidney failure or death assessed between 26 weeks and 54 months after randomization., Analytical Approach: Multivariable linear mixed-effects models with participant-specific slope and intercept to estimate the association of change in proteinuria over 26 weeks while receiving treatment with the subsequent slope of change in eGFR. Multivariable time-varying Cox proportional hazards models were used to estimate the association of changes in proteinuria with time to the composite outcome., Results: 138 of 192 trial participants were included. Changes in proteinuria over 26 weeks were significantly related to eGFR slope. A 1-unit reduction in log-transformed urinary protein-creatinine ratio was associated with a 3.90mL/min/1.73m 2 per year increase in eGFR (95% CI, 2.01-5.79). This difference remained significant after adjusting for complete remission. There was an analogous relationship between time-varying proteinuria and time to the composite outcome: the HR per 1-unit reduction in log-transformed urinary protein-creatinine ratio was 0.23 (95% CI, 0.12-0.44)., Limitations: Limited to individuals with steroid-resistant FSGS followed up for a maximum of 5 years., Conclusions: These findings provide evidence for the benefit of urinary protein reduction in FSGS. Reductions in proteinuria warrant further evaluation as a potential surrogate for preservation of kidney function that may inform the design of future clinical trials., (Copyright © 2020 National Kidney Foundation, Inc. All rights reserved.)