KEY POINTS:C3 glomerulopathy and immune complex-associated membranoproliferative glomerulonephritis in children have similar degrees of proteinuria, hypoalbuminemia, hypertension, and hypocomplementemia at diagnosis. C3 glomerulopathy and immune complex-associated membranoproliferative glomerulonephritis in children progress similarly to a composite outcome of CKD, dialysis, or kidney transplantation. A low level of C3 at baseline is associated with achieving the composite outcome. BACKGROUND:C3 glomerulopathy (C3G) and immune complex-associated membranoproliferative glomerulonephritis (IC-MPGN) are rare complement-mediated kidney diseases with a high risk of progression to kidney failure. Little is known about the natural history of these diseases in children, limiting our understanding of risk factors for progressive kidney disease. METHODS:Using a computable phenotype algorithm, a pediatric cohort with C3G or IC-MPGN was identified at seven institutions in PEDSnet, a national network of pediatric health systems which aggregate electronic health record data and collaborate on pragmatic research studies. Discrete data elements were captured from electronic health records, and additional clinical and histopathologic data were extracted by standardized chart review by pediatric nephrologists. Biopsy diagnosis was classified as C3G or IC-MPGN by applying an algorithm on the basis of immunofluorescence and electron microscopy and supplemented with manual chart review. Kaplan-Meier survival curves were used to compare the risk of reaching a composite kidney outcome of 50% reduction in eGFR, initiation of maintenance dialysis, or kidney transplantation. RESULTS:Of 204 patients with membranoproliferative glomerulonephritis identified by the computable phenotype algorithm and chart review, 159 could be further classified as C3G or IC-MPGN on the basis of available biopsy data. There were no significant differences in baseline serum albumin, C3 level, urine protein/creatinine ratio, or eGFR between C3G and IC-MPGN. Patients with C3G and IC-MPGN had similar rates of progression to the composite kidney outcome, and a low serum C3 level at baseline was associated with this composite outcome. CONCLUSION:Using large-scale, real-world multi-institutional data, we investigated the natural history of a large contemporary cohort of children with membranoproliferative glomerulonephritis. Because patients classified as having C3G compared with IC-MPGN had similar baseline clinical characteristics and rates of progressive disease despite untargeted treatment approaches, the availability of newer complement-targeted agents hold the promise of benefit to this population.

IntroductionAcross Latin America (LA), accessibility and affordability of kidney replacement therapy varies, but the prevalence of treated kidney failure generally lags behind higher income regions. Hemodialysis (HD) is more common than peritoneal dialysis (PD) in most LA countries. Expanding PD may help increase dialysis access in acute and chronic kidney disease. This study explored trends in existing kidney replacement therapy programs in LA and the opportunities and challenges for improving PD services from the perspective of physicians.MethodsQualitative data were collected using open-ended, semistructured interviews. Physician participants were recruited from trainees attending a Saving Young Lives workshop on acute kidney injury and acute PD. Thematic analysis was used to identify emergent themes.ResultsThere were 15 study participants. We identified and explored two main themes: (1) Physicians face many barriers to adequately caring for all dialysis patients, including high costs, geography, equipment and supply limitations, and lack of specialists; and (2) Increasing dialysis access through PD presents opportunities and challenges.ConclusionsWhile there are some dialysis programs in LA in which all patients have access to adequate care and dialysis is fully funded, there are many programs with inadequate capacity and funding. PD presents an opportunity to improve dialysis access in LA, particularly for currently underserved patient populations, but challenges related to staff training, supply access, and patient factors must be addressed for PD programs to be sustainable.

Background Recurrence of focal segmental glomerulosclerosis (rFSGS) remains a major complication and a challenge to study treatment efficacy due to lack of granular data in a sufficient sample size. Aggregated data from electronic health records can provide such data. Methods We applied computational phenotypes to data from 11 large pediatric health systems in the USA, to identify treatments used and remission outcomes in children with rFSGS after renal transplantation. Additional data were collected by chart review. We performed both linear and non-linear multivariable Cox regression analyses with penalized splines to allow for time-varying predictors. Based on effect sizes from the hazard ratios, we then calculated a sample size needed for a future randomized clinical trial. Results Plasmapheresis was used in 101/107 (94%) patients, followed by anti-CD20 agents in 84 (78%), Low-Density-Lipoprotein (LDL)-apheresis in 22 (20%) and CTLA4Igs in 8 (7%). In linear multivariable models, complete remission was associated with more plasmapheresis sessions. In non-linear models, more doses or sessions of all the above treatments were associated with complete remission or any remission (partial or complete). Penalized spline curves for complete or any remission showed greatest yield within 5 doses of anti-CD20 agents but increasing yield with more doses/sessions of CTLA4Igs or LDL-apheresis. Based on observed hazard ratios, a prospective randomized trial of plasmapheresis vs LDL-apheresis would require 155 participants to have 80% power. Conclusions Increased doses/sessions or additional therapies for rFSGS associated with more favorable outcomes. Non-linear modelling identified when further increases did not improve outcomes.

Air pollution is increasingly recognized as a risk factor for progression of kidney disease; however, few studies have examined its impact among patients with primary glomerular disorders. To address this knowledge gap, we previously reported positive associations between fine particulate matter ≤ 2.5μm in aerodynamic diameter (PM2.5) and black carbon with kidney disease progression in an observational cohort of children and adults (n = 925) with primary glomerular diseases, namely minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and IgA nephropathy. In the current study, we leverage the same cohort to (1) identify additional air pollutants that may be associated with kidney disease progression using data from the National Center for Atmospheric Research (NCAR); (2) determine whether the association between baseline air pollution exposure and kidney disease progression is maintained over a longer follow-up period; and (3) assess whether associations identified in our previously published findings remain when using NCAR pollutant data. In this retrospective cohort study, we obtained air pollutant concentration data from NCAR based on participant residential census tract at enrollment. For each census tract and pollutant, we aggregated daily pollutant concentrations to annual averages. We used Cox proportional hazards models to estimate associations between average baseline pollutant exposure and time to kidney disease progression, defined as a 40

Idiopathic nephrotic syndrome (INS) is a podocyte disease triggered by immune-derived factors. Endothelial activation occurs in this context, but whether the activated endothelium contributes to podocyte injury is unknown. We tested the hypothesis that CD93, a protein primarily expressed in the endothelium, is a contributory factor of podocyte injury. We studied 460 patients with INS and 150 with other podocytopathies. CD93 was analyzed in kidney tissue, urine, and serum samples. We tested the efficacy of CD93 blockade in vitro and in vivo and investigated the relationship between soluble CD93 and clinical outcomes in human INS. CD93 was highly expressed by glomerular endothelial cells (GEnCs) in human INS, and INS sera stimulated cultured human GEnCs to release CD93. Mechanistically, soluble CD93 mediated podocyte activation via β1 integrin/FAK signaling in cultured human podocytes. CD93 blockade mitigated the activation of cultured human podocytes and albumin permeability in human GEnC-podocyte cocultures as well as albuminuria, glomerulosclerosis, and podocyte loss in two models of nephrotic syndrome: podocyte-specific transforming growth factor-β1 signaling (PodTgfbr1) mice and adriamycin-treated mice. Cd93 knockout mice showed less proteinuria and glomerulosclerosis, compared with controls, after adriamycin injection. In patients with INS, soluble CD93 was high in urine in ~90% and 50% of patients in relapse and remission, respectively. High urinary CD93 was associated with faster decline in kidney function and slower response to immunosuppression. Soluble and glomerular CD93 was also elevated in other podocytopathies. We conclude that soluble CD93 contributes to podocyte injury.

IgA nephropathy (IgAN), IgA vasculitis (IgAV), focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), and minimal change disease (MCD) account for the majority of idiopathic glomerulo-nephropathies (GN). These disorders involve immune system dysregulation and have a complex genetic architecture. Currently, there are no adequately powered blood transcriptomic datasets coupled to genetic data from patients with GN that can delineate disease-context specific genetic effects on the blood immune cell transcriptome. We performed whole genome sequencing coupled with bulk blood transcriptome sequencing on 1,822 participants from the CureGN study, a prospective cohort of participants with a kidney biopsy diagnosis of primary GN. We generated disease-context specific transcriptome-wide maps of gene expression QTL (eQTL), splicing QTL (sQTL), and double strand RNA-editing QTL (edQTL) for FSGS (N=447), IgAN (N=403), IgAV (N=123), MCD (N=408), and MN (N=441), as well as cross-disease maps for all 1,822 participants. Our QTL mapping identified 16,068 eGenes, 4,644 sGenes and 4,611 edQTLs with an FDR<0.05 in at least one GN type. Approximately 5-10% of the QTL signals were unique to a specific GN type, while ~90% were shared between at least two conditions. Colocalization analysis demonstrated that ~80% of shared eGenes between traits also shared the same causal variants, whereas ~2% had distinct causal variants, suggesting context-specific regulatory effects. Cross-phenotype QTL mapping uncovered 6,466 eGenes, 2,705 sGenes and 5,321 edQTLs not previously detected in GTEx. Age, eGFR, and proteinuria-interaction QTL analyses identified hundreds of loci modified by age or disease severity. Lastly, integrative analyses with GWAS nominated new candidate genes for each of the five GN types under study. In summary, we generated comprehensive maps of GN-context-specific genetic effects on the blood transcriptome, providing a powerful new resource for integrative gene discovery studies of primary GN.

Idiopathic nephrotic syndrome (INS) is among the most common glomerular diseases in children with standard first line treatment of glucocorticoids. However, there has been no definitive treatment that can completely cure disease with few side effects for steroid resistant INS patients. Voclosporin (VCS) is a second generation calcineurin inhibitor (CNI) approved in multiple countries for the treatment of adults with active lupus nephritis. VCS does not require therapeutic drug monitoring due to an improved pharmacokinetic profile compared to other CNIs. Based on this, we assessed the ability of VCS to ameliorate proteinuria and hypoalbuminemia in a non-inflammatory glomerular disease using an animal model of NS. Rats received 50 mg/kg puromycin aminonucleoside (PAN) IV to induce NS. Rats were gavaged BID with vehicle or VCS (4 mg/kg/dose), a clinically relevant dose. Outcome measures included proteinuria, hypoalbuminemia, serum lipid profiles, glomerular podocyte injury, renal tubular injury, and hypercoagulopathy. Human podocytes were also treated with PAN +/- VCS and assessed for cell viability and stress using XTT and LDH release assays. VCS treatment significantly ameliorated PAN-induced proteinuria (61

BACKGROUND:Rituximab (RTX) is often used in children with nephrotic syndrome (NS), but there is lack of consensus on its dose among pediatric nephrologists. This study aimed to assess its efficacy in controlling NS and impact on healthcare utilization in children with NS. MATERIALS AND METHODS:This is a retrospective multicenter study of children with primary NS who were treated with RTX between 2013 and 2017. Summary statistics were used to describe the data. Variables were analyzed using Fisher's exact test or Mann-Whitney U test where indicated. RESULTS:The study included 50 children from 6 centers. At 12 months, 71.5% of steroid-sensitive NS (SSNS) patients and 37.5% of steroid-resistant NS (SRNS) patients achieved sustained remission. The median time to relapse was 16 months for the SSNS group and 7 months for the SRNS group. The median time to relapse was 7 months when receiving 1 infusion vs. 17 months for those receiving 2 RTX infusions. The rate of hospital admissions per patient-year significantly decreased from 0.53 to 0.11 after RTX treatment, without an increase in infection-related admissions. CONCLUSION:RTX is largely an effective treatment in children with SSNS leading to long remission periods and a substantial decrease in hospitalizations, with a low risk of serious infections.

OBJECTIVE:Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis often leads to severe kidney damage. To better understand ANCA-associated glomerulonephritis (AAGN) and identify potential new therapeutic targets, we performed comprehensive transcriptomic and compartmental proteomic analysis of kidney biopsies from 23 patients in the transcriptomic cohort, 10 in the proteomic cohort, and 5 healthy controls for each comparison. METHODS:Bulk RNA sequencing was performed on formalin-fixed paraffin-embedded kidney biopsies. Differentially expressed genes and pathways were identified using DESeq2, Ingenuity Pathway Analysis, and gene set enrichment analysis (GSEA). Correlations between gene expression and histologic features were assessed. Proteomic analysis was conducted via mass spectrometry of laser-microdissected glomerular and tubulointerstitial compartments to identify differentially abundant proteins and enriched pathways. RESULTS:In AAGN, 347 genes were up-regulated and 134 down-regulated compared to controls, including IL17D, CXCR2, IL7R, and CD163. Notably, several tripartite motif (TRIM) family genes were up-regulated. GSEA revealed broad immune cell enrichment and activation of proinflammatory interleukin (IL)-12, IL-17, and IL-18 signaling. Additionally, specific pathways correlated with histologic features (r ≥ 0.6), including enrichment of the complement cascade in histologically normal glomeruli, suggesting complement activation precedes visible structural damage. Conversely, STAT3/TRIM25 signaling correlated with glomerulosclerosis, IL-23 with necrotizing glomeruli, and FAT10 (UBD) signaling with interstitial fibrosis and tubular atrophy. Proteomics identified 63 differentially abundant proteins in the tubulointerstitium and 271 in glomeruli, with key network activators overlapping across data sets. CONCLUSION:This study uncovered a complex intrarenal immune landscape in AAGN, featuring diverse immune cell involvement and pathways associated with progressive damage. Our findings highlight potential therapeutic targets for further investigation, including IL-17, IL-8, and IL-23.

Pediatric patients with chronic kidney disease (CKD) are treated with nonspecific therapies such as renin-angiotensin-aldosterone system inhibitors; however, there are no approved therapies to slow the progression of pediatric CKD across its diverse etiologies. Sodium-glucose cotransporter-2 inhibitors (SGLT2is) have demonstrated efficacy in slowing the rate of decline in estimated glomerular filtration rate and CKD progression in adults. These therapies hold the promise of similar clinical benefit for pediatric patients with CKD by potentially delaying progression to kidney failure. However, clinical data informing the efficacy, safety, and dosing of these products in pediatric patients with CKD are lacking. To address this issue, a 1.5-day workshop was convened by the Kidney Health Initiative and NephCure, with participation from stakeholders that included regulators, National Institutes of Health representatives, trialists, clinicians and investigators, industry representatives, patient advocates, and caregivers. The goal of the workshop was to elucidate the challenges and strategize approaches to evaluate the use of SGLT2is in pediatric patients with CKD. To this end, presentations and discussions at the workshop focused on the data supporting the degree to which the course of CKD and expected treatment responses between adult and pediatric populations with CKD are similar, and hence, the degree to which, if any, data from the trials of SGLT2is in adults could be extrapolated to pediatric patients with CKD. Discussions also focused on trial design feasibility, end points, gaps in knowledge, and safety considerations for SGLT2is in pediatric CKD. The workshop proposed pathways to advance the evaluation of SGLT2is as therapeutic agents to treat glomerular and nonglomerular pediatric CKD while identifying remaining challenges and research priorities.

Introduction:Idiopathic nephrotic syndrome (INS) is associated with important kidney and cardiovascular morbidities. We tested the hypothesis that serum syndecan-1, a marker of endothelial glycocalyx injury, can help identify patients at risk for unfavorable kidney and cardiovascular outcomes. Methods:We included 348 children and adults with INS (n = 35 unbiopsied, n = 141 minimal change disease [MCD] and n = 172 focal segmental glomerulosclerosis [FSGS]) from the Nephrotic Syndrome Study Network (NEPTUNE) cohort and 34 healthy participants (n = 22 adults, n = 12 children). We measured baseline serum syndecan-1 levels using an enzyme-linked immunosorbent assay and evaluated their relationship with kidney and cardiovascular outcomes. We performed in vitro studies to test whether INS sera and different therapeutics may alter syndecan-1 expression in human glomerular endothelial cells (GEnC). Results:Serum syndecan-1 was higher in patients with INS than in controls and was high in approximately one-third of patients without proteinuria or with subnephrotic proteinuria. Patients receiving steroids, regardless of disease activity, showed higher syndecan-1 than those off immunosuppression. Syndecan-1 was higher in proteinuric patients with MCD than in FSGS. At the time of serum collection, syndecan-1 modestly correlated with proteinuria but not with kidney function. In longitudinal analyses, serum syndecan-1 was associated with the composite of 40% decline in kidney function or kidney failure and with dyslipidemia. Compared with controls, INS sera in relapse increased syndecan-1 expression in cultured GEnC, and this was partially or fully mitigated when dexamethasone or a metalloprotease inhibitor were added, respectively, to culture media. Conclusion:Baseline serum syndecan-1 is associated with unfavorable kidney outcomes and cardiovascular risk factors in INS.

ObjectivesTo assess the potential of a multi-institutional pediatric learning health system for comparative effectiveness research in pediatric-onset systemic lupus erythematosus (SLE), we characterized renin angiotensin aldosterone system (RAAS) inhibitor utilization and the feasibility of ascertaining key treatment indications and outcomes, including hypertension and proteinuria.MethodsWe identified children with SLE and lupus nephritis (LN) at 6 PEDSnet institutions using previously developed computable phenotypes. A reference population of controls without SLE was randomly sampled from the same rheumatology/nephrology clinics (N = 200 controls per site). We evaluated data completeness, plausibility, and conformance related to RAAS inhibitor treatment indications and outcomes: (a) percent of encounters with blood pressure (BP) readings, (b) percent of BP readings with paired height, (c) percent of patients with ≥1 urinalysis within 7 days of SLE diagnosis, (d) urinalyses for which proteinuria could be classified as normal or abnormal, and (e) RAAS inhibitor use.ResultsThere were 1303 patients with SLE, including 457 with LN. BP measurements were available at 62% of encounters, of which 96% were paired with a height within 90 days. BP distributions were higher in patients with SLE and LN compared to controls without SLE. One third of SLE patients had a hypertension diagnosis. 60%-83% of patients at each site had a urinalysis protein measurement within 7 days of SLE diagnosis. A normal or abnormal result for proteinuria could be derived for 96% of measurements, and nearly all patients with LN had ≥1 abnormal result (range 94%-100% by site). RAAS inhibitors were prescribed to 31% of SLE and 71% of LN patients (range 60%-84% by site). Hypertension, elevated BP or proteinuria was identified in 90% of SLE cases at the time of RAAS inhibitor initiation.ConclusionWe demonstrated the feasibility of ascertaining health measurement data relevant to pediatric lupus treatment and outcomes in a pediatric learning health system, as well as hospital-level variation in RAAS inhibitor use. This work will facilitate more efficient multi-institutional comparative effectiveness research and also highlights opportunities for increased treatment standardization.

The concept of a Learning Health System (LHS) has been widely discussed in academic literature, yet its practical implementation remains a challenge. This paper describes the institutional journey, leadership structure, data governance policies, and technical innovations that together support a scalable and sustainable Research-Oriented LHS. Additionally, we propose an expanded data vision that aligns with interdisciplinary and translational research needs. Supplementary materials provide technical details for those interested in implementing such a model.

BACKGROUND:Although congenital abnormalities of the kidney and urinary tract (CAKUT) is the leading cause of childhood-onset chronic kidney disease and kidney failure, comprehensive information on the disease burden among children and adolescents globally is lacking. We aim to report the trends and socioeconomic inequality of CAKUT burden for people aged 0-24 years from 1990 to 2019. METHODS:We reported the prevalence, mortality and disability-adjusted life-years (DALYs) for CAKUT based on the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, quantified the association of disease burden and socio-demographic index (SDI), and calculated the slope index of inequality, the relative index of inequality and concentration index. RESULTS:In 2019, the global prevalence, mortality and DALYs of CAKUT among individuals aged 0-24 years were 167.11 (95% confidence interval 166.97, 167.25), 0.30 (0.29, 0.30) and 32.22 (32.16, 32.29), respectively, per 100 000 population. The greatest prevalence, mortality and DALYs were recorded in the 0-4 years age group. The greatest mortality and DALYs were recorded in low SDI countries and territories. During 1990 to 2019, the prevalence, mortality and DALYs decreased globally, while in low and low-middle countries and territories the reduction was much less slower. India, Nigeria and Pakistan had the highest DALYs. Saudi Arabia and China exhibited a markedly decrease of CAKUT burden. Globally for every 0.1 increase in SDI, there was a 20.53% reduction in mortality and a 16.31% decrease in DALYs, but a 0.38% rise in prevalence. CONCLUSIONS:Inequality for disease burden of varying SDI was increasing globally. Thus, specific preventive and health service measures are needed to reduce the global burden from CAKUT.

Air pollution is a global problem and a major contributor to adverse health outcomes in patients of all ages. Most research has focused on the adverse effects of air pollution on cardiopulmonary events such as myocardial infarction, stroke and lung disease, with less attention given to kidney outcomes. In recent years, there is emerging evidence that air pollution contributes to the onset and progression of chronic kidney disease and, specifically, glomerular disease. This has been confirmed in epidemiological studies performed around the world. In this review, we summarize: (i) the major sources and components of air pollution; (ii) published reports detailing the relationship between air pollution exposure and the incidence and the clinical course of chronic kidney disease; and (iii) the existing literature assessing the impact of air pollution on the progression of primary glomerular diseases. We highlight important gaps in knowledge and the need for future collaborative work involving environmental scientists, epidemiologists and nephrologists to better understand the contribution of air pollution to the increasing number of people worldwide with chronic kidney disease. This work is important because air pollution exposure represents a potentially modifiable risk factor for chronic kidney disease progression that can be addressed by regulatory action, personal behaviors and implementation of interventions to prevent or limit exposure.