Association of COVID-19 Versus COVID-19 Vaccination With Kidney Function and Disease Activity in Primary Glomerular Disease: A Report of the Cure Glomerulonephropathy Study.

RATIONALE & OBJECTIVE: Patients with glomerular disease (GN) may be at increased risk of severe COVID-19, yet concerns over vaccines causing disease relapse may lead to vaccine hesitancy. We examined the associations of COVID-19 with longitudinal kidney function and proteinuria and compared these with similar associations with COVID-19 vaccination. STUDY DESIGN: Observational cohort study from July 1, 2021, to January 1, 2023. SETTING & PARTICIPANTS: A prospective observational study network of 71 centers from North America and Europe (CureGN) with children and adults with primary minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy. EXPOSURE: COVID-19 and COVID-19 vaccination. OUTCOME: Repeated measure of estimated glomerular filtration rate (eGFR); recurrent time-to-event outcome of GN disease worsening as defined by doubling of the urinary protein-creatinine ratio (UPCR) to at least 1.5g/g or increase in dipstick urine protein by 2 ordinal levels to 3+(300mg/dL) or above. ANALYTICAL APPROACH: Interrupted time series analysis for eGFR. Prognostic matched sequential stratification recurrent event analysis for GN disease worsening. RESULTS: Among 2,055 participants, 722 (35%) reported COVID-19 infection; of these, 92 (13%) were hospitalized, and 3 died (<1%). The eGFR slope before COVID-19 infection was-1.40mL/min/1.73m2 (± 0.29 SD); within 6 months after COVID-19 infection, the eGFR slope was-4.26mL/min/1.73m2 (± 3.02 SD), which was not significantly different (P=0.34). COVID-19 was associated with increased risk of worsening GN disease activity (HR, 1.35 [95% CI, 1.01-1.80]). Vaccination was not associated with a change in eGFR (-1.34mL/min/1.73m2±0.15 SD vs-2.16mL/min/1.73m2±1.74 SD; P=0.6) or subsequent GN disease worsening (HR 1.02 [95% CI, 0.79-1.33]) in this cohort. LIMITATIONS: Infrequent or short follow-up. CONCLUSIONS: Among patients with primary GN, COVID-19 infection was severe for 1 in 8 cases and was associated with subsequent worsening of GN disease activity, as defined by proteinuria. By contrast, vaccination against COVID-19 was not associated with change in disease activity or kidney function decline. These results support COVID-19 vaccination for patients with GN. PLAIN-LANGUAGE SUMMARY: In this cohort study of 2,055 patients with minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy, COVID-19 resulted in hospitalization or death for 1 in 8 cases and was associated with a 35% increase in risk for worsening proteinuria. By contrast, vaccination did not appear to adversely affect kidney function or proteinuria. Our data support vaccination for COVID-19 in patients with glomerular disease.

Pediatric contributions and lessons learned from the NEPTUNE cohort study.

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.

Growth in children with nephrotic syndrome: a post hoc analysis of the NEPTUNE study.

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 (ß - 7.5 × 10-6, CI - 1.2 × 10-5, - 3 × 10-6, p = 0.001) and incident cases of NS (vs. prevalent) (ß - 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 (ß 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.

Longitudinal analysis of blood pressure and lipids in childhood nephrotic syndrome.

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.

Vaccine Attitudes and COVID-19 Vaccine Intention Among Parents of Children With Kidney Disease or Primary Hypertension.

RATIONALE & OBJECTIVE: Children with kidney disease and primary hypertension may be more vulnerable to COVID-19. We examined COVID-19 vaccine hesitancy among parents of children with chronic kidney disease or hypertension. STUDY DESIGN: Sequential explanatory mixed-methods design; survey followed by in-depth interviews. SETTING & PARTICIPANTS: Parents of children aged <18 years with kidney disease or primary hypertension within a large pediatric practice. EXPOSURE: Parental attitudes toward general childhood and influenza vaccines assessed by the Vaccine Hesitancy Scale. Kidney disease classification, demographic and socioeconomic factors, experiences with COVID-19, COVID-19 mitigation activities and self-efficacy, and sources of vaccine information. OUTCOME: Willingness to vaccinate child against COVID-19. ANALYTICAL APPROACH: Analysis of variance (ANOVA) test to compare parental attitudes toward general childhood and influenza vaccination with attitudes toward COVID-19 vaccination. Multinomial logistic regression to assess predictors of willingness to vaccinate against COVID-19. Thematic analysis of interview data to characterize influences on parental attitudes. RESULTS: Of the participants, 207 parents completed the survey (39% of approached): 75 (36%) were willing, 80 (39%) unsure, and 52 (25%) unwilling to vaccinate their child against COVID-19. Hesitancy toward general childhood and influenza vaccines was highest among the unwilling group (P < 0.001). More highly educated parents more likely to be willing to vaccinate their children, while Black race was associated with being more likely to be unwilling. Rushed COVID-19 vaccine development as well as fear of serious and unknown long-term side effects were themes that differed across the parental groups that were willing, unsure, or unwilling to vaccinate their children. Although doctors and health care teams are trusted sources of vaccine information, perceptions of benefit versus harm and experiences with doctors differed among these 3 groups. The need for additional information on COVID-19 vaccines was greatest among those unwilling or unsure about vaccinating. LIMITATIONS: Generalizability may be limited. CONCLUSIONS: Two-thirds of parents of children with kidney disease or hypertension were unsure or unwilling to vaccinate their child against COVID-19. Higher hesitancy toward routine childhood and influenza vaccination was associated with hesitancy toward COVID-19 vaccines. Enhanced communication of vaccine information relevant to kidney patients in an accessible manner should be examined as a means to reduce vaccine hesitancy. PLAIN-LANGUAGE SUMMARY: Children with kidney disease or hypertension may do worse with COVID-19. As there are now effective vaccines to protect children from COVID-19, we wanted to find out what parents think about COVID-19 vaccines and what influences their attitudes. We surveyed and then interviewed parents of children who had received a kidney transplant, were receiving maintenance dialysis, had chronic kidney disease, or had hypertension. We found that two-thirds of parents were hesitant to vaccinate their children. Their reasons varied, but the key issues included the need for information pertinent to their child and a consistent message from doctors and other health care providers. These findings may inform an effective vaccine campaign to protect children with kidney disease and hypertension.

Determinants of medication adherence in childhood nephrotic syndrome and associations of adherence with clinical outcomes.

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.

Plasma exchange in ANCA-associated vasculitis: the pro position.

Plasma exchange (PLEX) is capable of removing significant amounts of circulating antibodies. In anti-neutrophil cytoplasmic antibody-associated vasculitis, PLEX was reserved for patients with severe presentation forms such as rapidly progressive glomerulonephritis and pulmonary haemorrhage. The Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis (PEXIVAS) trial included all comers with a glomerular filtration rate <50 mL/min/1.73 m2 and thus aimed to answer the question of whether PLEX is an option for patients with no relevant kidney function impairment or not. PEXIVAS revealed that after a follow-up of almost 3 years, routine administration of PLEX does not provide an additional benefit to reduce the rate of a composite comprising end-stage kidney disease or death. In the absence of histological parameters, it is tempting to speculate whether PLEX is effective or not in those with a potential for renal recovery. A subset of patients presented with alveolar haemorrhage, and there was a trend towards a better outcome of such cases receiving PLEX. This would be in line with observational studies reporting a recovery of alveolar haemorrhage following extracorporeal treatment. In this PRO part of the debate, we highlight the shortcomings of the PEXIVAS trial and stimulate further research paths, which in our eyes are necessary before abandoning PLEX from the therapeutic armamentarium.

APOL1 genotype-associated morphologic changes among patients with focal segmental glomerulosclerosis.

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.

A dual efficacy-implementation trial of a novel mobile application for childhood nephrotic syndrome management: the UrApp for childhood nephrotic syndrome management pilot study protocol (UrApp pilot study).

BACKGROUND: Idiopathic nephrotic syndrome has a relapsing-remitting course in the majority of pediatric patients, demanding vigilant monitoring and self-management. A novel, expert-designed, user-informed mobile application (app), UrApp©, was created to support management tasks, including home urine protein monitoring. METHODS: The UrApp Pilot Study (ClinicalTrials.gov, NCT04075656) is a randomized trial comparing UrApp-supported nephrotic syndrome management with standard-of-care with parallel process evaluation of the intervention delivery. Sixty caregivers of children with newly diagnosed, steroid-sensitive nephrotic syndrome will be randomized 1:1 to UrApp-supported care or standard-of-care. Follow-up will be 1 year, with primary outcomes of adherence to urine monitoring and medications assessed at 6 and 12 months. Secondary outcomes at 6 and 12 months include self-efficacy, quality-of-life, hospitalizations and delayed relapse diagnoses. A mixed-methods approach will evaluate UrApp engagement, use retention, features used, user perceptions, and contextual barriers and facilitators of UrApp use. User behavior will be assessed for relationships to the primary and secondary outcomes. A Stakeholder Committee of volunteer trial participants, clinicians, and engineers will examine the trial results and design a pragmatic UrApp-enhanced nephrotic syndrome intervention with potential for wide implementation. The final UrApp intervention will be tested in a user-centered hybrid effectiveness-implementation trial designed with stakeholder input. DISCUSSION: The UrApp Pilot Study examines the efficacy of a novel app designed specifically for nephrotic syndrome. The protocol involves dual efficacy and process evaluation aims to increase efficiency and incorporates the stakeholders' perspective in formative assessment to inform intervention redesign and the design of a future user-centered trial. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04075656. Registered on September 2, 2019, https://clinicaltrials.gov/ct2/show/NCT04075656.

Health-related quality of life in glomerular disease.

There is scant literature describing the effect of glomerular disease on health-related quality of life (HRQOL). The Cure Glomerulonephropathy study (CureGN) is an international longitudinal cohort study of children and adults with four primary glomerular diseases (minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and IgA nephropathy). HRQOL is systematically assessed using items from the Patient-Reported Outcomes Measurement Informative System (PROMIS). We assessed the relationship between HRQOL and demographic and clinical variables in 478 children and 1115 adults at the time of enrollment into CureGN. Domains measured by PROMIS items included global assessments of health, mobility, anxiety, fatigue, and sleep impairment, as well as a derived composite measure incorporating all measured domains. Multivariable models were created that explained 7 to 32% of variance in HRQOL. Patient-reported edema consistently had the strongest and most robust association with each measured domain of HRQOL in multivariable analysis (adjusted ß [95% CI] for composite PROMIS score in children, -5.2 [-7.1 to -3.4]; for composite PROMIS score in adults, -6.1 [-7.4 to -4.9]). Female sex, weight (particularly obesity), and estimated glomerular filtration rate were also associated with some, but not all, domains of HRQOL. Primary diagnosis, disease duration, and exposure to immunosuppression were not associated with HRQOL after adjustment. Sensitivity analyses and interaction testing demonstrated no significant association between disease duration or immunosuppression and any measured domain of HRQOL. Thus, patient-reported edema has a consistent negative association with HRQOL in patients with primary glomerular diseases, with substantially greater impact than other demographic and clinical variables.

Renal allograft loss due to renal vascular thrombosis in the US pediatric renal transplantation.

BACKGROUND: Renal vascular thrombosis (RVT) is a major cause of early allograft loss in the first year following pediatric kidney transplantation. We examined recent trends in allograft loss due to RVT and identified associated risk factors. METHODS: We identified 14,640 kidney-only transplants performed between 1995 and 2014 with follow-up until June 30, 2016, in 13,758 pediatric patients aged < 19 years from the US Renal Data System. We examined the 1-year incidence of allograft loss due to RVT by year of transplant, and plotted the trend over time. Cox proportional hazards models were used to investigate the relationship between year of transplant as well as recipient, donor, and transplant characteristics with allograft loss due to RVT. RESULTS: The incidence of allograft loss due to RVT consistently declined among pediatric kidney transplant performed between 1995 and 2014. Among transplants performed between 1995 and 2004, 128/7542 (1.7%) allografts were lost due to RVT compared to 53/7098 (0.8%) among transplants performed between 2005 and 2014; average 1-year cumulative incidence was 1.5% (95% CI, 1.3-1.9%) and 0.6% (95% CI, 0.5-0.8%), respectively. Increased risk for allograft loss due to RVT was associated with en bloc kidney transplantation (HR, 3.42; 95% CI 1.38-8.43) and cold ischemia time ≥ 12 h (HR, 1.78; 95% CI, 1.15-2.76). Interestingly, these risk factors were more prevalent in the latter decade. CONCLUSIONS: The incidence of allograft loss due to RVT significantly and continuously declined among pediatric kidney transplants performed between 1995 and 2014. The causes for this improvement are unclear in the present analysis.

Development of a novel mobile application to detect urine protein for nephrotic syndrome disease monitoring.

BACKGROUND: Home monitoring of urine protein is a critical component of disease management in childhood nephrotic syndrome. We describe the development of a novel mobile application, UrApp - Nephrotic Syndrome Manager, to aid disease monitoring. METHODS: UrApp was iteratively developed by a panel of two pediatric nephrologists and three research engineers from May 2017 to October 2018 for Apple iPhones. App features were devised by this expert panel to support urine monitoring and other home care tasks. Each feature and user-app interface element was systematically reviewed by the panel and iteratively redesigned to remove anticipated use issues. The app prototype was then refined based on two rounds of usability testing and semi-structured user interviews with a total of 20 caregivers and adolescent patients. The analytic function of UrApp in providing a camera read of the urine test strip was compared to a standard urinalysis machine using 88 patient urine samples and three iPhones, model versions 6S and 7. Exact agreement and weighted kappa were calculated between the UrApp and urinalysis machine reads. RESULTS: The final UrApp features include: camera read of a urine test strip; analysis of urine protein trends and alerts for new disease relapse/remission; transmission of urine protein results to providers; education materials; and medication reminders. During the second round of UrApp usability testing, all users were able to perform each of the functions without error and all perceived UrApp to be helpful and indicated that they would use UrApp. UrApp camera results had 97% exact agreement and an overall weighted kappa value of 0.91 (95% CI, 0.85-0.97) compared with standard urinalysis machine interpretation. CONCLUSIONS: UrApp was specifically designed to support patients and families living with nephrotic syndrome by supporting disease monitoring and home management tasks. The technically innovative feature that makes this possible is the use of a smartphone camera to read the urine test strip. This novel tool has the potential to improve disease monitoring and reduce management burden.

Mortality and Allograft Loss Trends Among US Pediatric Kidney Transplant Recipients With and Without Focal Segmental Glomerulosclerosis.

BACKGROUND: Pediatric patients with focal segmental glomerulosclerosis (FSGS) have high rates of disease recurrence and allograft failure after kidney transplantation, but there are few data for long-term survival posttransplantation. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 12,303 pediatric patients (aged <18 years), including 1,408 (11%) patients with FSGS, who received a first kidney transplant in 1990 through 2009 and were followed up through June 2015 were identified from the US Renal Data System database. PREDICTORS: Primary cause of end-stage renal disease, FSGS or other. OUTCOMES: All-cause patient mortality and allograft loss. RESULTS: All-cause mortality significantly improved for patients with FSGS who underwent transplantation in the 2000s versus the 1990s (6.72 vs 12.24 deaths/1,000 patient-years; HR, 0.55; 95% CI, 0.39-0.78; P<0.001). Reductions in allograft loss were less dramatic (75.91 vs 89.05 events/1,000 patient-years; HR, 0.85; 95% CI, 0.74-0.98; P=0.02). After adjusting for baseline characteristics at the time of transplantation, patients with FSGS had similar rates of death compared with patients without FSGS (HRs of 0.81 [P=0.6] and 1.06 [P=0.2] among those who underwent transplantation in the 2000s and 1990s, respectively) despite higher rates of allograft loss (HRs of 1.17 [P=0.03] and 1.27 [P<0.001], respectively). Among patients who underwent transplantation in the 2000s, further adjustment for allograft failure as a time-varying covariate demonstrated a lower rate of death among patients with FSGS compared with those without FSGS (HR, 0.70; P=0.02). LIMITATIONS: Lack of information about certain risk factors for mortality, including duration of chronic kidney disease; missing data; and potential primary disease misclassification. CONCLUSIONS: Survival of pediatric kidney transplant recipients with FSGS improved between the 1990s and 2000s and was similar to that of recipients without FSGS. Interestingly, adjustment for allograft failure showed greater survival for pediatric patients with FSGS who underwent transplantation in the 2000s as compared with others, suggesting that effective interventions to decrease allograft loss due to disease recurrence may improve patient survival.

Ofatumumab for the treatment of childhood nephrotic syndrome.

BACKGROUND: Ofatumumab is a humanized anti-CD20 monoclonal antibody that has recently garnered interest as a potential therapeutic agent for nephrotic syndrome. We report our center's experience in administering ofatumumab to five pediatric patients with idiopathic nephrotic syndrome. METHODS: Between March 2015 and November 2016, five patients were treated with ofatumumab. One patient had post-transplant recurrent focal segmental glomerulosclerosis (FSGS) which had been resistant to plasmapheresis and numerous immunosuppressive agents. Four patients had nephrotic syndrome in their native kidneys, one with initial steroid-resistant disease and the others with subsequent development of steroid resistance. Two of the patients were treated with a desensitization protocol after experiencing hypersensitivity reactions to ofatumumab. RESULTS: One patient did not complete ofatumumab treatment due to infusion reactions. Of the four remaining patients, three achieved complete remission after treatment, and one achieved partial remission. One of the patients achieving complete remission represents the first reported case of successful treatment of post-transplant recurrent FSGS using ofatumumab. Two patients who received ofatumumab with our desensitization protocol were able to complete their treatments after initially experiencing hypersensitivity reactions. CONCLUSIONS: Ofatumumab may be an effective treatment for refractory childhood nephrotic syndrome and post-transplant recurrent FSGS. A desensitization protocol may be helpful to address hypersensitivity reactions.

Design of a User-Centered Electronic Health Tool for Glomerular Disease Management.

Introduction: Patients with primary glomerular disease (GN) have unique management needs. We describe the design of a user-centered, patient-facing electronic health (eHealth) tool to support GN management. Methods: We surveyed patients and GN expert nephrologists on disease management tasks, educational needs, and barriers and facilitators of eHealth tool use. Results were summarized and presented to patients, nephrologists, engineers, and a behavioral and implementation science expert in stakeholder meetings to jointly design an eHealth tool. Key themes from the meetings are described using rapid qualitative analysis. Results: Sixty-six patients with minimal change disease, focal segmental glomerulosclerosis, IgA nephropathy, and membranous nephropathy responded to the survey, as well as 25 nephrologists from the NIH-funded Cure Glomerulonephropathy study network. Overall, patients performed fewer management tasks and acknowledged fewer informational needs than recommended by nephrologists. Patients were more knowledgeable about eHealth tools than nephrologists. Nine patient stakeholders reflected on the survey findings and noted a lack of awareness of key recommended management tasks and receiving little guidance from nephrologists on using eHealth. Key themes and concepts from the stakeholder meetings about eHealth tool development included the need for customizable design, trustworthy sources, seamless integration with other apps and clinical workflow, and reliable data tracking. The final design of our eHealth tool, the UrApp System, has 5 core features: "Profile" generates personalized data tracking, educational information, facilitation with provider discussions and inputting other preferences; "Data Tracking" displays patient health data with the ability to communicate important trends to patients and nephrologists; "Resources" provides trusted education information in a personalized manner; "Calendar" displays key events and generate reminders; and "Journal" facilitates information documentation using written or audio notes. Conclusion: Our theory- and evidenced-based, stakeholder-engaged design process created designs for an eHealth tool to support the unique needs of patients with GN, optimized for effectiveness and implementation.

Improving Hepatitis B Screening Prior to Rituximab: A Quality Improvement Project.

Rituximab, used in the treatment of some rheumatic and kidney diseases, can lead to hepatitis B virus (HBV) reactivation; HBV screening is recommended for those starting this medication. We aimed to improve by 50% the proportion of patients undergoing HBV screening by implementing multimodal interventions to support clinicians in this evidence-based practice. We conducted a quality improvement project from November 2020 to June 2022 at a tertiary care pediatric hospital system, including patients with rheumatic and/or kidney diseases starting rituximab. Multimodal interventions targeting clinicians included electronic health tools (dot phrase, display of screening recommendations and screening results in rituximab order sets/therapy plans), educational meetings, and e-mail/paper reminders. The primary outcome was the proportion of patients with complete HBV screening, while the secondary outcome was utilization of each laboratory component, tracked using statistical process control charts. Pre- and post-intervention data were compared using Fisher's test. One hundred eighty-two patients who had been prescribed rituximab were included, of which 98 (54%) were post-intervention. The proportions of patients undergoing complete HBV screening (6% vs. 44%; p < 0.001), HBsAg collection (60% vs. 79%; p = 0.006), anti-HBsAb collection (14% vs. 54%; p < 0.001), and total anti-HBcAb collection (8% vs. 52%; p < 0.001) were significantly higher in the post-intervention period. Improvement was sustained over 18 months, with shifts and/or data points above the control limits in all measures. Forty-five patients were HBV-non-immune. In this study, multimodal interventions including electronic health tools and education of the provider significantly increased the proportion of patients screened for HBV prior to rituximab and identified immunization opportunities.

Estimation of childhood nephrotic syndrome incidence: data from the atlanta metropolitan statistical area and meta-analysis of worldwide cases.

BACKGROUND: Epidemiological data on childhood idiopathic nephrotic syndrome (INS) are limited. We estimated childhood INS incidence in a racially and ethnically diverse U.S. population and performed a meta-analysis of published reports to examine differences by race, ethnicity, and time. METHODS: One hundred seventy-five children aged 1-17 years living in the Atlanta Metropolitan Statistical Area (MSA) between 2013 and 2018 were identified by retrospective chart review. Annual INS incidence was estimated by dividing cases by population data from the Georgia Department of Public Health. We calculated pooled incidence estimates using random-effects regression models in a meta-analysis of the current and prior studies. Subgroup incidence estimates by race, ethnicity, and time were compared and tested for heterogeneity. RESULTS: One hundred seventy-five children aged 1-17 were diagnosed with INS between 2013 and 2018 in the Atlanta MSA. Average annual incidence was 2.13/100,000 (95% CI, 1.83-2.47). Twenty-four studies were included in meta-analysis. Our study was the only one to report incidence for Hispanic children, 2.13/100,000/y (95% CI, 1.40-3.10). In meta-analysis, incidence was highest in Asian children (7.14/ 100,000/y; 95% CI, 4.73-9.54), followed by Black (3.53/100,000/y; 95% CI, 2.93-4.12), and Caucasian (1.83/100,000/y; 95% CI, 1.52-2.14). Annual incidence in the U.S. was stable comparing studies performed before and after 1984, 2.05 vs. 2.26/100,000 (p 0.08). CONCLUSIONS: Risk of INS may be higher among Asian and Black children compared to White children. Incidence appears stable over time in the U.S. Future studies should use standardized methodology and assess the contribution of demographic and genetic factors to INS incidence and long-term outcomes.

Comparing Kidney Health Outcomes in Children, Adolescents, and Adults With Focal Segmental Glomerulosclerosis.

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.

Grip Strength in Adults and Children with Cystinosis.

INTRODUCTION: Chronic kidney disease (CKD) is associated with impaired muscle strength. Patients with cystinosis have an increased risk for impaired muscle strength because of early development of CKD and cystinosis-induced myopathy. This study assesses muscle strength in patients with cystinosis and investigates risk factors of decreased muscle strength. METHODS: Adult and pediatric patients were recruited from Cystinosis Research Network conferences and a large pediatric nephrology clinic between 2017 and 2019. Patients and caregivers completed questionnaires on demographic characteristics, disease course, daily physical activity, and neuromuscular symptoms. Grip strength was assessed using a dynameter and calculated z-scores for age and sex were assessed for associations with patient characteristics. RESULTS: We included 76 patients with a mean grip strength z-score of -2.1 (SD, 1.1), which was lower than seen in patients with CKD without cystinosis. Male sex and delayed cysteamine initiation were independently associated with impaired grip strength. Among adults, a low level of physical activity was associated with lower grip strength z score, but no association was found in children. A third of the patients reported neuromuscular symptoms, with swallowing issues associated with lower grip strength. There was no significant correlation between eGFR and grip strength z-score. CONCLUSION: Patients with cystinosis have impaired muscle strength compared with healthy control subjects and patients with CKD. This impairment is greater in male patients and in patients with late initiation of cysteamine therapy and is associated with lower physical activity. Further studies investigating the effect of different types of physical activities, optimizing cysteamine therapy, and other interventions are needed.