BACKGROUND:Clinical trials in rare glomerular disease may establish short-term treatment efficacy but are limited by small sample sizes and short study duration. Observational data are needed to assess longer-term outcomes and can provide insights into real-world prescribing practices. This study applied modern statistical methods to real-world data from the Cure Glomerulonephropathy (CureGN) network to compare the effectiveness of rituximab and calcineurin inhibitors on long-term primary membranous nephropathy outcomes. METHODS:CureGN participants with biopsy-confirmed primary membranous nephropathy who initiated either of the two treatments at least 6 months after any previous immunosuppressant exposure were eligible. Inverse-probability-of-treatment weighting balanced covariates at treatment initiation. Inverse-probability-of-censoring weights accounted for censoring individuals if another immunosuppressant was started during follow-up. Outcomes included time from treatment initiation to composite kidney disease progression (40% decline in eGFR, kidney replacement therapy, or eGFR <15), proteinuria remission, and relapse following remission. Hazard ratios and differences in restricted mean survival times were estimated. RESULTS:325 treatment initiations across 250 unique participants were eligible, with median follow-up 53 months (25th-75th percentile: 24-79). Participants on calcineurin inhibitors had significantly higher risks of disease progression (HR=2.81; 95% CI: 1.16, 6.80). Hazard ratios for proteinuria remission (HR=0.77; 95% CI: 0.50, 1.17) and relapse (HR=1.42, 95% CI: 0.69, 2.92) had wide confidence intervals. CONCLUSIONS:Rituximab was associated with better kidney function preservation than calcineurin inhibitors over long follow-up. Proteinuria remission and relapse results favored rituximab but did not reach statistical significance. Long-term treatment comparative effectiveness in rare diseases can be evaluated with real-world data.

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

Rationale & Objective:Mobile health technologies such as text messaging have been used to support self-management in chronic disease. This study sought to understand the use of and responsiveness to text messaging for data collection in an international longitudinal observational study. Study Design:A longitudinal text messaging program was administered in the Cure Glomerulonephropathy Network, an observational cohort study of primary glomerulonephropathies. Consented participants were sent monthly texts querying symptoms, medication adherence, relapses, or remissions. Participants responded via text. Setting & Participants:Adults enrolled in the Cure Glomerulonephropathy Network from October 23, 2020, to April 30, 2024, participated remotely via text messaging. Predictors:Age, histologic diagnosis, months since diagnosis using kidney biopsy, education level, and English as the primary language. Outcome:Program reach (proportion who did not opt out), response rate, and ongoing engagement were assessed. Analytical Approach:Multivariable logistic regression models were fitted to assess associations between responsiveness to text and participant characteristics. Results:71% (n = 948) did not opt out, and of those, 54% (512/948) responded to at least 1 text. Responders were more likely to be younger (OR, 0.97 per additional year; 95% CI, 0.97-0.98) and had more formal education (high school education: OR, 0.63 and 95% CI, 0.41-0.98, compared with some college) than nonresponders. Those who did not speak English primarily were less likely to respond (OR, 0.64; 95% CI, 0.42-0.98) than primary English speakers. In an unadjusted subgroup analysis of those with census tract data, responders resided in communities with greater community resources than nonresponders (P < 0.001). Limitations:Unable to determine reasons for nonresponse to text messaging. Conclusions:Although text messaging does not require a smartphone and may reduce some barriers to research participation, we found that more vulnerable and older patients were less likely to respond. Additional efforts are needed to support targeted engagement with these participants to ensure that data collection overall remains equitable.

Key PointsAdolescents and young adults with glomerular disease have unique clinical features distinct from children and older adults.Patterns of relapse, remission, and changes in kidney function differ by age and glomerular disease type.Traditional pediatric-adult cutoffs often overlook key differences; care and research should reflect a continuum across the lifespan.BackgroundGlomerular disease (GD) is a prominent cause of kidney disease in adolescents and young adults (AYAs), yet there is limited information on how this population fares compared with children and older adults.MethodsWe analyzed data from Cure Glomerulonephropathy, a prospective cohort of patients of all ages with biopsy-proven GD. Patients with minimal change disease (MCD), FSGS, and IgA nephropathy (IgAN) were included. Patients were stratified into pediatric (<= 13), AYA (14-25), and adult (>= 26) groups and compared by demographic, clinical, and disease characteristics. Associations between age group and relapse rate, change in kidney function, and time to remission were assessed using multivariate negative binomial, linear mixed effects, and Cox proportional hazards models, respectively, stratified by disease type.ResultsOur study included 1868 patients (562 pediatric, 397 AYA, and 909 adults). The median follow-up time was 4.9 years. Adults with MCD had fewer relapses (incidence rate ratio [IRR], 0.61; 95% confidence interval [CI], 0.41 to 0.91; P = 0.01), while there was no difference between pediatric participants with MCD (IRR, 1.23; 95% CI, 0.85 to 1.79; P = 0.28) compared with AYA. Adults with IgAN had fewer relapses than AYA (IRR, 0.55; 95% CI, 0.33 to 0.94; P = 0.03). AYA had faster decline in kidney function compared with pediatric participants with FSGS (1.7 versus 0.3 ml/min per 1.73 m2 per year, P = 0.008) and IgAN (1.5 versus 0.1 ml/min per 1.73 m2 increase per year, P = 0.002). Pediatric participants with MCD achieved first observed remission sooner compared with AYA (hazard ratio, 2.18; 95% CI, 1.03 to 4.63; P = 0.04). Adults with IgAN were slower to achieve first observed remission compared with AYA (hazard ratio, 0.58; 95% CI, 0.37 to 0.91; P = 0.02).ConclusionsAYA with GD exhibit distinct clinical patterns compared with the pediatric and adult age groups, underscoring the need to approach care and research along an age-related continuum rather than a binary framework.

Lower urinary tract dysfunction presents with a wide range of bothersome urinary symptoms, which are common in both men and women, with incidence and prevalence increasing with age. Individuals with lower urinary tract symptoms (LUTS) suffer from the chronicity of their symptoms, have a reduced quality of life, and experience high morbidity with associated medical conditions. Various treatment options exist, but many patients do not find satisfactory or lasting relief. The Symptoms of Lower Urinary Tract Dysfunction Research Network (LURN) was formed in 2012 with the goals of improving methods for assessing patient-reported experiences with LUTS; identifying and describing patient subtypes; and generating data, research tools and biological samples for future studies. LURN developed three self-report instruments for measuring LUTS. More than 1,000 men and women with LUTS seeking treatment were enrolled, and completed a baseline and interval assessments throughout a 12-month observational period. Findings from LURN studies showed that various biological, non-urological, psychosocial and behavioural factors contribute to the development and persistence of LUTS. Additionally, patients seeking care for LUTS often present with a wider variety of urological symptoms than previously thought. Diagnoses for these patients do not reliably fit into traditional categories such as overactive bladder or BPH. LURN has addressed its objectives by creating new, top-tier assessment tools; conducting studies to gather clinically relevant data to identify potential new and accurate patient subtypes; and collecting a wealth of data and biological samples for future research to continue subtype refinement.

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.

Introduction:Among patients with proteinuric glomerular diseases, there is a paucity of high-quality evidence and substantial variation in practice patterns among nephrologists. Our objective was to describe the clinical presentation, treatment patterns, and outcomes of patients with biopsy-proven glomerular diseases in a contemporary, well-phenotyped, diverse cohort. Methods:The Nephrotic Syndrome Study Network (NEPTUNE) is a prospective observational cohort study of children and adults with proteinuric glomerular diseases enrolled at 23 centers in the USA and Canada since 2009. We included participants who underwent their first clinically indicated kidney biopsy demonstrating minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), or membranous nephropathy (MN). We described demographic and clinical characteristics at the time of biopsy and baseline visits. We analyzed treatment patterns for participants with and without immunosuppressive therapy (IST) use prior to biopsy. We described clinical outcomes including complete remission (CR) and proteinuria, stratified by IST use, at biopsy and up to 36 months' follow-up. Results:Among 507 NEPTUNE participants who underwent biopsy, 203 were classified as having FSGS, 193 as having MCD, and 111 as having MN. Corticosteroid exposure was high overall and highest among MCD patients. Substantial heterogeneity in treatment choices was evident, particularly among those initiating second-line therapy. The rate of kidney failure was highest, and CR rates were lowest, among patients with FSGS, who experienced ∼50% cumulative probability of first remission at 36 months after biopsy. At 36 months, 49.5% of all patients were not in CR; 19.3% were not in CR despite being on IST. Additionally, 20.2% of patients had proteinuria >1.5 g/g; among those on IST at their 36-month visit, 26.3% had UPCR >1.5 g/g. Conclusion:A substantial proportion of patients were not in remission and had persistent proteinuria despite being on IST 3 years after their first biopsy.

INTRODUCTION AND HYPOTHESIS:Depressive and anxiety symptoms are known risk factors for lower urinary tract symptoms (LUTS). To inform prevention and treatment strategies, this research examined whether greater emotional support seeking weakened associations of affective symptoms with LUTS and poorer bladder health. METHODS:Data were collected from women in the USA who participated in the RISE FOR HEALTH study of bladder health. In this cross-sectional analysis (analytic sample n = 1444), self-reported LUTS, perceived bladder health, and perceived impact of bladder health on five domains of living (social and occupational activities, travel, physical activities, intimacy, and emotions) were separately regressed on depressive symptoms, anxiety symptoms, and emotional support seeking. Interaction tests examined whether emotional support seeking modified associations of affective symptoms with LUTS and bladder health. RESULTS:Report of worse depressive symptoms, worse anxiety symptoms, and lower levels of engagement in emotional support seeking were associated with more frequent LUTS, poorer perceived bladder health, and lower perceived positive impact of bladder health on each domain of living. Emotional support seeking was not associated with LUTS and bladder health outcomes when adjusting for affective symptoms, and did not modify associations of affective symptoms with LUTS and bladder health outcomes. CONCLUSIONS:Intervention research to prevent LUTS and promote bladder health can test strategies that include screening and providing timely treatment of affective symptoms. Health care providers treating women for LUTS can screen for affective symptoms and make referrals to ensure that both the physical health and the mental health needs of patients are being met.

Background:Erectile function (EF) and its associated covariates have not been extensively studied in a large covariate of patients seeking treatment for lower urinary tract symptoms (LUTS). Our objective is to determine the relationship between urinary symptoms and comorbidities with erectile dysfunction (ED) in 447 treatment-seeking men with LUTS. Methods:Data from the Symptoms of Lower Urinary Tract Dysfunction Research Network (LURN) observational cohort study were analyzed using multivariable logistic regression models to quantify the relationship between LUTS and ED. Models also included anxiety, depression, obesity, cardiovascular disease (CVD), diabetes, and medication use. Results:Men reporting sexual activity were younger (median age 61 vs. 69 years) and had lower prevalence of diabetes and CVD (13% and 15%, respectively) compared with men reporting no sexual activity (24% for diabetes and 27% for CVD). Among sexually-active participants, higher odds of ED were associated with diabetes [odds ratio (OR) =2.4; 95% confidence interval (CI): 1.1-5.0], age (per 5 years, OR =1.4; 95% CI: 1.2-1.6), urinary incontinence (UI) (OR =1.2; 95% CI: 1.0-1.4), and anxiety (per 10 T-score units, OR =1.4; 95% CI: 1.0-2.1). Low erectile confidence was related to older age in non-sexually-active men (per 5 years, OR =1.5; 95% CI: 1.2-1.8). In sexually-active men, anxiety (per 10 T-score units, OR =1.6; 95% CI: 1.1-2.4), age (OR =1.3; 95% CI: 1.2-1.5), PDE5-inhibitor use (OR =2.1, 95% CI: 1.0-4.3), and diabetes (OR =2.2; 95% CI: 1.1-4.7) were also associated with low erectile confidence. Conclusions:The association of UI with ED highlights the importance of screening men with UI for ED. Modifiable health variables, such as anxiety and diabetes, were related to ED and erectile confidence in treatment-seeking men with LUTS.

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.

KEY POINTS:Adolescents and young adults with glomerular disease have unique clinical features distinct from children and older adults. Patterns of relapse, remission, and changes in kidney function differ by age and glomerular disease type. Traditional pediatric-adult cutoffs often overlook key differences; care and research should reflect a continuum across the lifespan. BACKGROUND:Glomerular disease (GD) is a prominent cause of kidney disease in adolescents and young adults (AYAs), yet there is limited information on how this population fares compared with children and older adults. METHODS:We analyzed data from Cure Glomerulonephropathy, a prospective cohort of patients of all ages with biopsy-proven GD. Patients with minimal change disease (MCD), FSGS, and IgA nephropathy (IgAN) were included. Patients were stratified into pediatric (≤13), AYA (14-25), and adult (≥26) groups and compared by demographic, clinical, and disease characteristics. Associations between age group and relapse rate, change in kidney function, and time to remission were assessed using multivariate negative binomial, linear mixed effects, and Cox proportional hazards models, respectively, stratified by disease type. RESULTS:Our study included 1868 patients (562 pediatric, 397 AYA, and 909 adults). The median follow-up time was 4.9 years. Adults with MCD had fewer relapses (incidence rate ratio [IRR], 0.61; 95% confidence interval [CI], 0.41 to 0.91; P = 0.01), while there was no difference between pediatric participants with MCD (IRR, 1.23; 95% CI, 0.85 to 1.79; P = 0.28) compared with AYA. Adults with IgAN had fewer relapses than AYA (IRR, 0.55; 95% CI, 0.33 to 0.94; P = 0.03). AYA had faster decline in kidney function compared with pediatric participants with FSGS (1.7 versus 0.3 ml/min per 1.73 m 2 per year, P = 0.008) and IgAN (1.5 versus 0.1 ml/min per 1.73 m 2 increase per year, P = 0.002). Pediatric participants with MCD achieved first observed remission sooner compared with AYA (hazard ratio, 2.18; 95% CI, 1.03 to 4.63; P = 0.04). Adults with IgAN were slower to achieve first observed remission compared with AYA (hazard ratio, 0.58; 95% CI, 0.37 to 0.91; P = 0.02). CONCLUSIONS:AYA with GD exhibit distinct clinical patterns compared with the pediatric and adult age groups, underscoring the need to approach care and research along an age-related continuum rather than a binary framework.

Background: Little is known about women's decisions around toileting for urination and how those decisions influence moment-to-moment behaviors to manage bladder needs. The new smartphone app "Where I Go" captures such nuanced and granular data in real-world environments. Objective: This study aims to describe participant engagement with "Where I Go", variation in novel parameters collected, and readiness for the data collection tool's use in population-based studies. Methods: "Where I Go" has three components: (1) real-time data, (2) short look-back periods (3-4 h), and (3) event location (GPS recorded at each interaction). The sample size was 44 women. Recording of real-time toileting events and responding to look-back questions was measured over 2 days of data collection. The participant's self-entered location descriptions and the automatic GPS recordings were compared. Results: A total of 44 women with an average age of 44 (range 21-85) years interacted with the app. Real-time reporting of at least 1 toileting event per day was high (38/44, 86%, on day 1 and 40/44, 91%, on day 2) with a median of 5 (IQR 3-7 on day 1 and IQR 3-8 on day 2) toileting events recorded each day. Toileting most commonly occurred at home (85/140, 61%, on day 1 and 129/171, 75%, on day 2) due to a need to go (114/140, 66%, on day 1 and 153/171, 74%, on day 2). The most common reasons for delaying toileting were "work duties" (33/140, 21%, on day 1 and 21/171, 11%, on day 2) and "errands or traveling" (19/140, 12%, on day 1 and 19/171, 10%, on day 2). Response to at least 1 look-back notification was similarly high (41/44, 93%, on day 1 and 42/44, 95%, on day 2), with number of responses higher on average on day 2 compared with day 1 (mean on day 1=3.2, 95% CI 3.0-3.5; mean on day 2=4.3, 95% CI 3.9-4.7; P<.001). Median additional toileting events reported on the look-back survey were 1 (IQR 1-2) and 2 (IQR 1-2) on days 1 and 2, respectively. Overall concordance between self-reported location recording and GPS was 76% (188/247). Participants reported lower urge ratings when at home versus away when reporting real-time toileting (median rating 61, IQR 41-84 vs 72, IQR 56-98), and daily fluid intake showed a small to medium positive correlation with toileting frequency (day 1 r=0.3, day 2 r=0.24). Toileting frequency reported in "Where I Go" showed a small positive correlation with the frequency item from the International Consultation on Incontinence Questionnaire (r=0.31 with day 1 toileting frequency and r=0.21 with day 2 toileting frequency). Conclusions: "Where I Go" has potential to increase the understanding of factors that affect women's toileting decisions and long-term bladder health. We anticipate its use as a data collection tool in population-based studies.

Introduction:Understanding how different symptoms co-occur and are correlated may provide insights into the pathophysiology of disease. The lack of group-to-individual generalizability of co-occurrence of symptoms was recently demonstrated by comparing intra-individual and inter-individual correlations in several psychological studies. Here, we investigate this phenomenon for lower urinary tract symptoms (LUTS). Methods:We analyzed data collected in the Symptoms of Lower Urinary Tract Dysfunction Research Network Recall Study. Participants responded to questions about their urinary symptoms for 25 consecutive days. These questions queried urologic symptoms including storage (urinary urgency, frequency, nocturia, and urinary incontinence), voiding (slow/weak stream), and post-micturition (incomplete emptying and post-micturition dribble) symptoms. We calculated Pearson correlation coefficients and cosine similarity measures and compared distributions of intra-individual and inter-individual (cohort) metrics. Results:Among 234 participants, distributions of intra-individual measures were 10-fold wider than those of inter-individual correlations. There are pairs of questions with distributions of correlations and cosine similarities containing individuals with extreme positive (>0.8) and extreme negative values (<-0.8). There are groups of participants with strong positive and negative correlations of urinary frequency and nocturia, urinary incontinence and weak flow, as well as strong negative and positive correlations of urinary frequency and dribbling. Information on these extreme groups is averaged out and lost in the inter-individual correlations. Conclusions:Lack of group-to-individual generalizability previously shown for psychological symptoms is confirmed for LUTS. Wealth of information on the co-occurrence and co-evolution of LUTS in the intra-individual correlations and cosine similarities corroborates heterogeneity of LUTS and can be useful for deep phenotyping and for identifying personalized treatments of LUTS.

Introduction:New equations developed in the USA for estimating glomerular filtration rate (GFR) eliminated race for adults and widened the age range for children and young adults. The European Kidney Function Consortium (EKFC) equation was also validated and updated for a US adult population. The aftereffects of adopting these new equations on previous research results among patients with glomerular disease are unknown. This study compared eGFR using old and new estimating equations and their impacts on eGFR-based outcomes. Methods:Longitudinal serum creatinine measurements from children and adults enrolled in the Nephrotic Syndrome Study Network (NEPTUNE) were used to calculate eGFR using old bedside Schwartz and CKD-EPI 2009 equations, new U25 and race-free CKD-EPI 2021 equations, and the EKFC equation. Time to disease progression (40% eGFR decline or kidney failure) outcomes were compared using Kaplan-Meier curves and Cox models and longitudinal eGFR outcomes were compared using linear mixed-effects models to assess effects of demographics, clinical characteristics, pathology descriptors, a serum and urine biomarker, and the APOL1 genetic trait. Results:N = 756 NEPTUNE study participants were included (median age 21 years, 41% female, and 25% who reported Black race). Disease progression outcomes were similar between using old versus new age-specific equations, whereas event rates were lower using EKFC. Survival curves were largely overlapping, and selected risk factor effects on disease progression were similar. Only sex and race effects on longitudinal eGFR differed between old versus new age-specific equations, whereas larger differences were observed for disease diagnosis effects when using EKFC. Conclusion:New U25 and race-free CKD-EPI 2021 equations had little impact on estimated GFR values and results of survival and longitudinal regression analyses. EKFC results differed and were likely driven by those with very high eGFR.

BACKGROUND:The Centers for Disease Control and Prevention (CDC) Environmental Justice Index Social-Environmental Ranking (EJI-SER) combines a Social Vulnerability Module (SV) with an Environmental Burden Module (EB) to characterize cumulative environmental and social burden at the census tract level. This analysis evaluates the association between EJI-SER and kidney outcomes in glomerular disease (GD) patients. METHODS:Cure Glomerulopathy (CureGN) is an observational cohort study of adults and children with biopsy-proven GD. EJI-SER is a percentile ranking by census tract, with a higher score indicating a more severe burden. Associations between EJI-SER and its components with kidney failure (initiation of kidney replacement therapy, transplant, or two estimated glomerular filtration rates [eGFRs] <15ml/min/1.73m2) and longitudinal eGFR were tested using multivariable Cox regression and linear mixed models, respectively, adjusted for demographics, histologic diagnosis, eGFR and urine protein to creatinine ratio at enrollment, and time from biopsy to enrollment. RESULTS:Among 1,149 participants with census tract data, the median (IQR) follow-up was 5.4 (3.0-7.0) years, the median (IQR) age at biopsy was 24 (10-48), and self-identified racial distribution was 5% Asian, 18% Black, and 70% White. Median (IQR) EJI-SER was 0.49 (0.26-0.75). EJI-SER scores in the lowest two quartiles were associated with a lower hazard of kidney failure compared to the highest quartile (adjusted HR [95% CI] 0.62 [0.36-1.08] and 0.43 [0.25-0.76] for EJI-SER 0-25% and >25-50% vs. >75%, respectively) and higher eGFR at enrolllment (adjusted mean 90.1 vs. 87.1 ml/min/1.73m2 for 0-25% vs. >75%, p=0.08). CONCLUSION:As captured by EJI-SER, higher environmental and social burdens are associated with lower eGFR and a higher risk of kidney failure in the CureGN cohort. This first use of the EJI-SER in GD demonstrates the need for additional investigation into social drivers of disparities in GD and policies and resources that address these structural inequities.

Focal segmental glomerulosclerosis (FSGS) is a rare condition that affects children and adults, lacks any approved therapy, and has a high risk of progression to kidney failure (KF). The PARASOL consortium was set up to establish evidence to inform adoption of feasible and clinically meaningful surrogate endpoints for FSGS clinical trials. PARASOL combined 9 registries of biopsy-proven or genetic FSGS patients from North America and Europe. Eligible participants required: (1) UPCR ≥1.5 g/g at any time post-biopsy or diagnosis or up to 3 months prior (index UPCR); (2) eGFR ≥30 ml/min up to 3 months prior to index UPCR; (3) ≥1 additional UPCR and eGFR measurement 3 to 24 months post-index; and (4) no evidence of KF (kidney replacement therapy, eGFR sustained <15 ml/min) prior to the first post-index measurements. Relationships between change in eGFR and proteinuria response (across various thresholds) in the first 24 months post-index and subsequent probability of kidney failure beyond 24 months were assessed using Cox proportional hazards models, using a landmark approach with a landmark time of 24 months post-index. Validation was performed among participants fulfilling the same criteria in the UK National Registry of Rare Kidney Diseases (RaDaR). PARASOL contained 1626 eligible participants, with median (IQR) follow-up time from kidney biopsy of 64.2 months (35.2, 103.1). At biopsy, median age was 19 years (IQR 7, 43), median UPCR was 3.8 g/g (IQR 2, 7.2) and median eGFR was 81 ml/min (IQR 54, 109). eGFR and the rate of eGFR decline were associated with KF hazard but were highly variable: sample size requirements for clinical trials using eGFR endpoints ranged from 500–1000 individuals per arm. Proteinuria reduction was strongly associated with reduced KF hazard. Using a UPCR responder threshold of 0.7 g/g, achieved in 406 participants, responders had an 85% lower hazard of kidney failure (HR = 0.15, 95% CI = 0.09–0.26) and a survival difference of +0.27 (95% CI 0.22–0.32) compared to non-responders, consistent in incident and prevalent subpopulations and in subgroups based on age and index proteinuria or eGFR level. Estimated sample size requirements for trials using this proteinuria endpoint was 100–200 per group. The findings were validated in RaDaR, which included 465 eligible participants. At index, RaDaR participants were older, median age 36 (14–55), with lower kidney function, median eGFR 71 ml/min (46–106), and higher proteinuria, median UPCR 5.3 g/g (2.7–8.9). Responder status based on UPCR at 24 months was similar to PARASOL. Stratifying by index UPCR into 1.5 to <3.5 g/g, 3.5 to <7.0 g/g and ≥7.0 g/g, in PARASOL 32%, 31%, and 34% achieved <0.7 g/g by 24 months compared with 25%, 42% and 29% in RaDaR (Fig. 1). At the 0.7 g/g threshold, adjusted hazard ratios and survival differences were similar to PARASOL at 0.07 (0.02–0.27) and 0.29 (0.22–0.36) respectively (Fig. 2), consistent in all subgroups analysed. For most therapeutic effect sizes, variability in eGFR within and between patients with FSGS means that sample size requirements for trials using eGFR or eGFR slope endpoints are unfeasibly large. In contrast, there was consistent and strong association of proteinuria reduction (a biologically plausible parameter) with higher KF-free survival. Proteinuria reduction is therefore a potential surrogate endpoint for FSGS clinical trials that is both feasible and clinically meaningful.