Frequently relapsing, steroid-dependent nephrotic syndrome (FRNS/SDNS) remains a therapeutic challenge. Rituximab, a B-cell-depleting agent, is effective and widely used for FRNS/SDNS, but its use can be limited by rare, serious adverse effects. Belimumab, a monoclonal antibody targeting B-cell activating factor (BAFF), is approved for treating adult systemic lupus erythematosus (SLE) and lupus nephritis (LN). We report a pediatric case of FRNS/SDNS refractory to conventional immunosuppressive regimens and intolerant of rituximab due to serious complications, who subsequently maintained complete remission for nearly one year after steroid withdrawal while receiving belimumab added to ongoing mycophenolate mofetil (MMF). This case suggests that belimumab combined with MMF is effective for refractory NS. However, as a single case report, its efficacy requires further strengthening through more cases.

B-cell-depleting agents like rituximab (RTX) are central to treating severe steroid-dependent idiopathic nephrotic syndrome (SDNS) and frequent relapses. However, RTX can induce anti-RTX antibodies (ARA) that compromise efficacy. Obinutuzumab, a fully humanized anti-CD20 antibody, may overcome RTX resistance. We evaluate obinutuzumab's safety and efficacy in pediatric SDNS patients who developed ARA after RTX. We conducted a retrospective study in two pediatric nephrology centers in Paris, France, including SDNS patients treated with RTX who developed ARA and subsequently received obinutuzumab. Thirty-two patients (median age 4.1years) were included, previously treated with a median of 2 RTX infusions (IQR 1-2). ARA were detected at 3.2months (range 0-17), following a median depletion of 2.9months (IQR 2.1-5.8); 13/32 had titers ≥ 100ng/mL. Obinutuzumab was given for short/failed RTX depletion (n = 19) or early relapse (n = 13). Six infusion reactions occurred but no serum sickness. B-cell depletion after obinutuzumab lasted 6.5months (IQR 5.6-8.1). Among 28 patients with baseline ARA at obinutuzumab infusion, 50% had titers ≥ 100ng/mL, with no difference in B-cell depletion (median 5.3 vs. 6.8months; p = 0.40), or relapse-free survival at 24months (75% vs. 46%; p = 0.10). Longitudinal ARA monitoring showed sustained positivity in 76.5% at 6months, and one patient > 100ng/mL at 24months. Obinutuzumab is an effective and well-tolerated option in the context of ARA, providing prolonged B-cell depletion. Further studies with ARA monitoring are needed to optimize anti-CD20 therapy.

The effects of rituximab on relapse of nephrotic syndrome in patients with adult-onset frequently relapsing nephrotic syndrome (FRNS) or steroid-dependent nephrotic syndrome (SDNS) remain uncertain. To evaluate the effects of rituximab for patients with FRNS or SDNS. Multicenter, double-blind, randomized, placebo-controlled trial conducted at 13 centers in Japan. Adults with FRNS or SDNS who had urine protein of less than 0.3 g/gCr were enrolled between September 1, 2020, and June 28, 2022. Final follow-up occurred on March 15, 2024. Patients were randomized to receive either intravenous rituximab, 375 mg/m2 (n = 36), or placebo (n = 36) at weeks 1, 2, and 25. Patients were followed up for 49 weeks. The primary outcome was the proportion of patients who were free of relapse of nephrotic syndrome at 49-week follow-up. Relapse was defined as urine protein of at least 1 g/gCr on 2 consecutive measurements. Among 72 randomized participants (mean age, 47.9 years; 56.1% female), 66 (92%) received the study drug at least once and were included in analyses. The relapse-free rate at week 49 was 87.4% (95% CI, 69.8%-95.1%) in the rituximab group and 38.0% (95% CI, 22.1%-53.8%) in the placebo group (P < .001 by 1-sided log-rank test). One of 18 secondary outcomes was statistically significant (favoring rituximab). The median relapse-free time in the rituximab group was greater than 49.0 weeks and in the placebo group was 30.8 weeks. A stratified Cox model showed a hazard ratio for relapse of 0.16 (95% CI, 0.05-0.46; P < .001) in the rituximab group compared with the placebo group. The most common adverse effect was infusion reaction (13 [40.6%] in the rituximab group and 1 [2.9%] in the placebo group). These results support use of rituximab to prevent relapse in adults with FRNS or SDNS. Japan Registry of Clinical Trials: jRCT2051200045; University Hospital Medical Information Network Clinical Trials Registry: UMIN000041475.

This study assessed the psychological distress, depression, and burden among primary caregivers of children with steroid-sensitive nephrotic syndrome (SSNS) and explored its association with disease severity and patient/caregiver demographics. Psychological assessment of primary caregivers of children aged 6months to 15years with SSNS was performed using General Health Questionnaire-12 for psychological distress, Beck Depression Inventory for depression, and Zarit Burden Interview-6 for caregiver burden. Out of 72 eligible caregivers, 60 were included. Severe depression, severe psychological distress, and significant caregiver burden were observed in 38.3%, 30%, and 61.7% of primary caregivers, respectively. Steroid-dependent nephrotic syndrome (SDNS) and disease duration over 24months increased severe psychological distress. Risk factors for caregiver depression included child < 7years, female gender, frequently relapsing nephrotic syndrome (FRNS)/SDNS, steroid use > 6months, > 4 relapses, and prior hospitalization. Caregiver burden was higher in younger age, FRNS/SDNS, hospitalization, and lower middle socio-economic status. Caregivers of children with SSNS experience significant psychological distress, depression, and financial burden.

Immunosuppressive drugs are required for childhood frequent-relapse nephrotic syndrome (FRNS), steroid-dependent NS (SDNS), or steroid-resistant NS (SRNS). However, the benefits of immunosuppressants need to be balanced with their known side effects. This study aimed to compare remission rates of FRNS, SDNS, and SRNS in children treated with cyclophosphamide versus cyclosporin A (Cy A). We retrospectively reviewed the medical records of children diagnosed with NS at Prince of Songkla University Hospital, Thailand. Remission rates and complications in patients with FRNS/SDNS and SRNS were compared among those treated with oral cyclophosphamide, Cy A, or cyclophosphamide followed by Cy A. Among 148 children (102 boys, 68.9%), the median age was 4.6years (IQR 2.5-8.4). FRNS, SDNS, and SRNS were diagnosed in 37 (25.0%), 50 (33.8%), and 61 (41.2%) children, respectively. Among 87 FRNS/SDNS patients, 67 were treated with cyclophosphamide, 2 with Cy A, and 18 with cyclophosphamide followed by Cy A. There were no statistically significant differences in remission rates or complications among the treatment groups. Among 61 SRNS patients, 27 were treated with cyclophosphamide, 11 with Cy A, and 23 with cyclophosphamide followed by Cy A. The remission rates were 29.6%, 72.7%, and 43.5%, respectively. Acute kidney injury (AKI) was reported in 14.8%, 18.2%, and 52.2% of patients, respectively. In FRNS/SDNS patients, remission rates were comparable between cyclophosphamide and Cy A treatments. In SRNS patients, Cy A treatment resulted in a higher remission rate than cyclophosphamide but was associated with a greater incidence of AKI.

Abstract Background and Aims Steroids induce remission in 90% of children with idiopathic nephrotic syndrome (INS). Some patients become steroid-dependent (SD) and require additional drugs like calcineurin inhibitors (CNI) to maintain remission. Due to the toxicity of these drugs, alternative interventions are needed. The anti-CD20 antibody rituximab has been effective as a steroid-sparing agent. Mycophenolate mofetil (MMF) is also effective in maintaining steroid-free remission, but studies are limited to a few uncontrolled trials with varying MMF doses. Method This is an open-label, two-parallel-arm, multi-center, superiority-controlled randomized clinical trial in SD-INS maintained in remission with oral glucocorticoids. Subjects were be randomized to either MMF (1.200 mg/m2) or single rituximab infusion (375 mg/m2). Glucocorticoids were tapered until complete withdrawal. The primary end-point is to detect as significant at the two-sided p-value of 0.01 with a power &amp;gt;0.8 a reduction in the risk of 2-years relapse. Results We randomized 160 children and young adults (aged 2–24 years) and we enrolled 156 subjects (Fig. 1A). At 2 years, 30 of 78 (37%) participants who received rituximab experienced relapse versus 22 of 78 (26%) who received MMF (odds ratio [OR], 1.45; 95% confidence interval [95% CI], 0.8 to 2.7) (Fig. 1B). No major adverse events ere reported. In a subset of patients (n = 56) we compared. The median age of the entire cohort was 9 years. Therefore, we defined the risk of 2-years relapse based on age at randomization. In &amp;gt;9 years cohort, 34% who received rituximab experienced relapse versus 28% who received MMF. In &amp;lt;9 years cohort, 41% who received rituximab experienced relapse versus 22% who received MMF (Fig. 1C and D). Conclusion A single dose of rituximab was not superior to MMF in maintaining remission at 2 years of follow-up in children and young adults with steroid-dependent nephrotic syndrome. Our findings also suggest that rituximab may be more effective in older subjects.

Rituximab maintains remission of complicated frequently relapsing or steroid-dependent nephrotic syndrome (FRNS/SDNS) by depleting peripheral B cells, but most patients eventually experience relapses after B cell recovery. We performed a multicenter, double-blind, randomized, placebo-controlled trial to assess rituximab’s efficacy and safety for childhood-onset uncomplicated FRNS/SDNS (without prior treatment with glucocorticoid-sparing immunosuppressive agents) with a follow-up study to assess rituximab’s long-term effect after B cell recovery. Patients were randomly assigned to receive either rituximab (375 mg/m2, maximum 500 mg, once weekly for 2 weeks) or placebo. The primary endpoint was the relapse-free period. Of 43 randomized patients, 40 received the intervention (18 rituximab, 22 placebo). The relapse-free period during the 1-year trial was significantly longer in the rituximab vs. placebo groups (median: 285 vs. 81 days; p < 0.001). Infusion reactions were more frequent in the rituximab group (p < 0.001), with no difference in adverse events incidence between the groups. Interestingly, the follow-up study demonstrated markedly higher 3-year cumulative relapse-free survival probability without further treatments in the rituximab vs. placebo groups (38% vs. 9%). A mini-systematic review with meta-analyses supported the findings. Rituximab is effective and well-tolerated, potentially leading to long-term remission with substantially high rates after B cell recovery for childhood-onset uncomplicated FRNS/SDNS.Trial registration JSKDC10, Clinical Trials Registry ID: jRCT1091220380; JSKDC10 follow-up study, Clinical Trials Registry ID: jRCT1050230024Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-19214-0.

Introduction: Rituximab (RTX) is a key therapeutic agent for maintaining remission in steroid-dependent nephrotic syndrome and frequently relapsing nephrotic syndrome, demonstrating both efficacy and safety. However, reliable biomarkers for predicting relapse remain under investigation. Methods: This single-center, retrospective, observational study included 70 patients who received RTX between January 2015 and January 2023. Patients were classified into two groups: the non-relapse group and the relapse group. Cox proportional hazards regression was used to analyze the associations between baseline clinical parameters and relapse risk, while Kaplan-Meier survival analysis was performed to estimate the recurrence-free survival rates. Results: This cohort of 70 pediatric patients (71.4% male; median age: 9.5 years, interquartile range: 8.5–12.6) exhibited a 24-month post-rituximab relapse rate of 32.9% (23/70). Multivariate analysis identified elevated baseline memory B-cell levels (adjusted hazard ratio [HR] = 1.103, 95% confidence interval [CI]: 1.045–1.164, p < 0.001), reduced baseline natural killer (NK) cell levels (adjusted HR = 0.866, 95% CI: 0.752–0.997, p = 0.045), and higher IgG levels at 3 months post-RTX (adjusted HR = 1.245, 95% CI: 1.080–1.435, p = 0.003) as independent predictors of relapse. Kaplan-Meier survival analysis revealed that patients with memory B-cell counts below 19.65% of baseline (n = 38) had significantly higher 24-month relapse-free survival compared to those with counts above this threshold (n = 32; 86.8% vs. 43.8%; χ2 = 13.918, p < 0.001). In contrast, patients with NK-cell levels below 6.45% of lymphocytes (n = 25) exhibited poorer 24-month relapse-free survival than those with higher NK-cell proportions (n = 45; 52.0% vs. 77.8%; χ2 = 6.395, p = 0.011). Similarly, patients with IgG levels below 5.74 g/L (n = 35) demonstrated significantly better relapse-free survival compared to those with higher levels (n = 35; 85.3% vs. 47.2%; χ2 = 11.030, p = 0.001). Conclusion: Baseline memory B-cell and NK-cell levels (pre-RTX), as well as IgG levels at 3 months post-RTX, were identified as predictive biomarkers for the 2-year relapse risk following RTX therapy. These findings may contribute to the development of personalized RTX treatment strategies.

To determine the cyclosporine trough (C0) and two-hour post-dose concentrations (C2) in children with nephrotic syndrome (NS) and study the factors influencing them. In this ambispective cohort study, children with NS (including frequently relapsing, steroid-dependent and steroid-resistant nephrotic syndrome) on cyclosporine therapy were enrolled. Clinical and laboratory data were recorded. C0 and C2 were estimated using liquid chromatography mass spectrometry. Among 27 patientswith amean (SD) age of 6.4 (4.1) years, the median (Q1, Q3) of C0 and C2 were 114.8 (86.1, 186.3) ng/mL and 661.6 (442.1, 884.6) ng/mL, respectively. At a mean (SD) cyclosporine dose of 4.1 (0.8) mg/kg/day, 12 (44%) patientshad C0 above and 4 (15%) below the therapeutic range (80-120ng/mL). C2 levels were outside the recommended ranges in 17 (63%) children, within range in 7 (26%), and below in 3 (11%).Capsule users had higher C0 than syrup users. Amlodipine therapy was associated with higher C0 levels. Nearly half the children had C0 and C2 levels outside the therapeutic range. Dosage form and amlodipine influenced C0, not C2 concentrations.

Although single-daily cyclosporine may offer an effective therapeutic option with increased compliance and reduced nephrotoxicity, response predictors and long-term outcomes following this regimen remain unclear in children with steroid-dependent nephrotic syndrome. A retrospective study was conducted between October 2005 and December 2021 on children with steroid-dependent nephrotic syndrome caused by minimal change disease (MCD) who were treated with preprandial single-daily cyclosporine to maintain 2-h post-dose levels of 500-700ng/mL. The primary endpoint was the time to treatment failure after single-daily cyclosporine initiation. The secondary endpoint was the long-term outcome at last visit. After initiating single-daily cyclosporine therapy in 48 children, 31 patients, including 18 who did not experience relapse during treatment, were able to discontinue steroids (response group), while 17 patients experienced treatment failure. The median time to the first relapse after nephrotic syndrome diagnosis was significantly shorter in the treatment failure group than in the response group (2.1 vs. 4.3months, p = 0.014). Multivariable Cox proportional hazard regression analysis identified two independent risk factors for treatment failure: early first relapse < 2.2months after nephrotic syndrome diagnosis (hazard ratio: 7.79, 95% confidence interval: 2.29-26.48, p = 0.001) and higher prior relapse rate (hazard ratio: 1.41 per episode increase, 95% confidence interval: 1.07-1.86, p = 0.016). None of the patients progressed to chronic kidney disease Stage 3 or higher. Single-daily cyclosporine may offer a promising treatment option for children with steroid-dependent nephrotic syndrome caused by MCD, particularly for those who do not experience early relapse following nephrotic syndrome diagnosis and have lower prior relapse rate.

Objective: To investigate the association between anti-rituximab antibodies (ARA) and relapse after rituximab (RTX) therapy in children with frequently relapsing or steroid-dependent nephrotic syndrome (FRNS or SDNS). Methods: A retrospective cohort study was conducted. Clinical and laboratory data were collected from 48 FRNS or SDNS children treated with RTX in the Department of Pediatrics, General Hospital of Eastern Theater Command, between April 2024 and October 2024. Data included RTX dosing frequency, relapse events, peripheral CD20⁺ B-cell counts, and ARA levels. With a 6-month observation period after the last RTX therapy, the children were divided into an ARA-positive group and an ARA-negative group based on ARA test results. Chi-square test, independent sample t-test, or Mann-Whitney U test were used to compare relapse rates and laboratory indicators between the two groups. The predictive value of ARA levels for relapse was evaluated using univariate receiver operating characteristic (ROC) curve analysis. Results: Among the 48 children (36 males, 12 females), the age of disease onset was 3.5 (2.0, 6.0) years, the ages at the first and last RTX treatments were 7.0 (5.0, 12.0) years and 9.5 (7.0, 13.0) years, respectively. The overall ARA positive rate was 29% (14/48). The relapse rate in the ARA-positive group was significantly higher than that in the negative group (P<0.05). The ARA level was 0.01 (0.01, 5.88) μg/L, and all 12 children with ARA levels >5.88 μg/L relapsed. ROC curve analysis showed that ARA levels predicted relapse after RTX treatment in FRNS or SDNS children with an area under the curve (AUC) of 0.73, sensitivity of 0.50, specificity of 1.00, and an optimal cut-off value of 5.02 μg/L. All children received single-dose RTX therapy, with no significant difference in treatment frequency between the two groups (P>0.05). At 3 months after the last rituximab therapy, CD20⁺ B cell counts were significantly higher in the ARA-positive group (P<0.05). During follow-up, 15% (7/48) of the children experienced infusion-related adverse reactions, with no significant difference in incidence between the two groups (P>0.05). Conclusion: ARA is significantly associated with relapse in FRNS or SDNS children after RTX therapy.

BackgroundRituximab (RTX) has gradually been accepted as a treatment for frequently relapsing nephrotic syndrome (FRNS) or steroid-dependent nephrotic syndrome (SDNS) in children, but no standardized recommendations for the dosage and combination therapy exist. Additionally, the efficacy and safety of low-dose RTX in FRNS/SDNS remain unclear, although it has been used to treat some autoimmune diseases.MethodsWe report a case series of 24 children diagnosed with FRNS/SDNS treated with low-dose RTX followed by mycophenolate mofetil (MMF) for maintenance of remission of nephrotic syndrome between August 2021 and February 2023. These patients were followed up for at least 12 months.ResultsThe mean total dose for the initial four administrations of low-dose RTX was 470.83 ± 62.41 mg, which was significantly lower than the calculated values for one standard dose (525.62 ± 125.62 mg; P = 0.006) and two standard doses (1051.2 ± 251.23 mg; P < 0.001). After treatment initiation, the median follow-up was 24.6 (16.8, 28.5) months. At the 1-year follow-up, no child had experienced treatment failure, and the relapse-free rate was 83.3%. At the last follow-up, two children had experienced treatment failure, with both having frequent relapses, and the relapse-free rate was 75%. Compared with the calculated standard dose of RTX, low-dose RTX followed by MMF was less costly. No serious adverse reactions were observed during RTX use or follow-up, except for one death due to delayed treatment of severe infection.ConclusionLow-dose RTX followed by MMF can extend the remission duration of FRNS/SDNS in children, and decrease the economic burden on families, while offering good safety.

BackgroundPatients with frequent relapsing or steroid-dependent nephrotic syndrome (FRSDNS) often maintain remission during the period of B lymphocyte depletion following rituximab (RTX) administration. However, a subset of patients may experience early relapse and subsequently develop refractory disease. In this retrospective study, we summarized the clinical characteristics and outcomes of patients who experienced early relapse during B lymphocyte depletion.MethodsThis was a retrospective cohort study. The relapse group included six FRSDNS cases with early relapse during B lymphocyte depletion, while the control group consisted of 15 patients without relapse. A comparative analysis was performed on the clinical characteristics and follow-up outcomes of the two groups.ResultsCompared with the control group, the relapse group exhibited a higher proportion of elevated CD4 + T cell levels (100% vs. 47%, P = 0.046) and lower doses glucocorticoid administration (83.3% vs. 26.7%, P = 0.046) at baseline. Following RTX injection, patients in the control group maintained remission within six months, and the number of relapses within the first year was higher in the relapse group than in the control group. [1.5 (1, 2.5) vs. 0 (0, 0)], Z= -3.708, P = 0.000)].ConclusionEarly-stage relapses were predominantly observed in patients who received lower doses glucocorticoids or had higher CD4 + lymphocyte levels at baseline. Patients experiencing early relapse demonstrated lower overall efficacy with RTX treatment.Clinical trial numbernot applicable.

Background and Objectives: The nephrotic syndrome (NS) is the most common acquired childhood kidney disease. Steroids represent the cornerstone of the therapeutic strategy, representing the first-line approach, but optimal therapeutic management is debated. This study aimed to compare different steroid therapeutic management protocols. Patients and Methods: A total of 140 NS pediatric patients were enrolled retrospectively. All the kids were divided among three different groups according to the three different steroid therapeutic schemes: 2240 mg/m2 (group 1), 3360 mg/m2 (group 2), or 3640 mg/m2 (group 3) and divided in frequently relapsing (FR-NS) or steroid-dependent (SD) NS. Results: Within group 1, 50% of the population developed FR-NS; 100% of those kids were between 2 and 6 years old. Within the second group, 54% of the patients developed FR-NS, and 83% of these kids were between 2 and 6 years old, i.e., 45% of the group population. Within group 3, 45% of the patients developed FR-NS, and 70% of these kids were among 2 and 6 years old, i.e., 32% of the group population. This group exhibits the lowest percentage (42%) of patients in the highest relapse category (≥5 relapses) compared to the other protocols, indicating that this protocol might be more effective at reducing the number of frequent relapses. No specific predictor factors of FR- or SD-NS were revealed in the studied cohort. Conclusions: A longer steroid scheme does not correlate with a better outcome, nor does it reduce the number of relapses or prevent steroid failure.

Nephrotic syndrome (NS) is a clinical condition characterized by massive proteinuria, hypoalbuminemia, edema, and hypercholesterolemia. Frequently relapsing NS, steroid-dependent NS, and steroid-resistant NS are categorized as problematic owing to treatment difficulties. These patients require prolonged high-dose steroid therapy or immunosuppressants, resulting in significant side effects. This study evaluated the nutritional status and laboratory characteristics of NS in children undergoing steroid and non-steroid therapies. This study is the first to assess the nutritional status and laboratory characteristics of children with difficult-to-treat NS who received steroid and non-steroid therapy at RSUDZA Banda Aceh. A cross-sectional study was conducted at the outpatient clinic and pediatric ward of Dr. Zainoel Abidin General Hospital, Banda Aceh, in 2019, which was a limitation because it was conducted during the Covid-19 pandemic so that the number of research subjects was limited, which could have caused bias in the study. Statistical analyses included the chi-square test or Fisher’s exact test for categorical variables and the independent sample t-test or Mann-Whitney test for numerical variables, with a 95% significance level (p &lt; 0,05). A total of 60 children aged 2–18 years participated in this study, with 29 receiving steroid therapy and 31 receiving non-steroid therapy. Urine protein levels and relapse incidence differed significantly between the groups (p &lt; 0,001). However, the serum albumin, urea, creatinine, calcium, and total cholesterol levels were not significantly different. No significant differences were observed in the laboratory characteristics between the steroid and non-steroid therapy groups. However, the non-steroid group exhibited a better urine protein status and fewer relapses, indicating potential therapeutic advantages.

A growing body of evidence supports the efficacy of the type I anti-CD20 monoclonal antibody, rituximab, in the management of children with frequently relapsing or steroid-dependent nephrotic syndrome. We examined temporal trends and described current patterns in the use of anti-CD20 antibodies and other corticosteroid-sparing drug therapies in a large multi-institutional population of children with nephrotic syndrome. Data came from PEDSnet, a clinical research network that aggregates electronic health record data at several children's healthcare organizations in the United States. Patients with at least one inpatient, emergency, or outpatient physician encounter between January 2010 and November 2022 who met our published computable phenotype algorithm for nephrotic conditions were included. Children with systemic lupus erythematosus or congenital/genetic nephrotic diagnoses were excluded. Treatments were measured from nephrotic syndrome diagnosis to kidney transplant or most recent encounter. Among 6,892,137 patients across 6 centers, 2962 met criteria for nephrotic conditions (0.4 per 1000 patients). 852 (28.8%) had at least one native kidney biopsy. Nearly half of the population was exposed to at least one steroid-sparing agent, most of whom had exposure to multiple agents. 524 (17.7%) patients were exposed to rituximab, and utilization of rituximab increased over the 12-year study period. Similar trends were observed for mycophenolate and tacrolimus. Concurrently, use of cyclosporine and cyclophosphamide decreased. Use of rituximab to manage nephrotic syndrome has steadily increased, and tacrolimus, mycophenolate, and rituximab are currently the most commonly used steroid-sparing agents for childhood nephrotic syndrome.

The efficacy and safety of rituximab in adult patients with steroid-dependent or frequent relapsing nephrotic syndrome: A retrospective study.

Autoantibodies against the podocyte protein nephrin were recently identified in a pediatric cohort primarily comprising steroid-sensitive (SSNS) and steroid-dependent (SDNS) nephrotic syndrome (NS). However, their prevalence across all NS subtypes, particularly in steroid-resistant nephrotic syndrome (SRNS), and their relation to therapy response need to be determined to advance pathophysiological understanding and refine treatment strategies. A multicenter cohort study measuring anti-nephrin autoantibodies in samples from children with SSNS, SDNS, nongenetic and genetic SRNS was conducted. Sixty-nine of 101 (68%) patients with SSNS, 19 of 67 (28%) patients with SDNS, 14 of 103 patients (14%) with non-genetic SRNS, and 1 of 62 patients (2%) with genetic SRNS were positive for anti-nephrin autoantibodies. The prevalence of anti-nephrin autoantibodies increased with presence of active disease in cases of SSNS and SDNS. Within the group of non-genetic SRNS patients with active disease, anti-nephrin positivity was found in 13 of 74 (18%) patients responding to intensified immunosuppression compared to none of 17 patients with multidrug-resistant SRNS. The prevalence of anti-nephrin antibodies is substantially higher in children with steroid responsive NS than in those with SRNS, suggesting that anti-nephrin antibodies primarily drive SSNS/SDNS. In contrast, NS due to podocyte gene mutations is primarily genotype-caused. Anti-nephrin autoantibodies may serve as a positive prognostic marker in pediatric NS, indicating a favorable response to immunosuppressive therapy.

Both tacrolimus (TAC) and mycophenolate mofetil (MMF) are recommended for children with frequently relapsing nephrotic syndrome (FRNS) or steroid-dependent nephrotic syndrome (SDNS). However, their comparative effectiveness and safety have not been evaluated through randomized clinical trials. To compare the effectiveness and safety of TAC and MMF in children with FRNS or SDNS. In this multicenter, open-label randomized clinical trial conducted at 12 pediatric nephrology centers across China, 270 children aged 2 to 18 years with FRNS or SDNS were allocated at a 1:1 ratio to treatment with either TAC or MMF. The study was conducted from November 2019 to July 2023, and data analysis was completed from July 2023 to March 2024. Patients received either TAC (0.025-0.050 mg/kg, orally twice daily) or MMF (10-15 mg/kg, orally twice daily) for 1 year, along with a tapering regimen of steroids. The primary end point was 1-year relapse-free survival. Relapse frequency, cumulative steroid dosage, and safety profiles were also evaluated. A total of 292 patients from 12 care centers were assessed for eligibility, and 270 patients were randomized to receive either TAC (n = 135) or MMF (n = 135). Among 270 patients, median (IQR) age was 6.91 (4.25-9.96) years, and 70 patients (25.9%) were female. Compared with MMF, the 1-year relapse-free survival rate in the TAC group was 1.86-fold higher (hazard ratio [HR], 2.86; 95% CI, 1.79-4.76; P < .001) in the intention-to-treat analysis. This difference was also significant after adjusting for the per-protocol analysis (HR, 2.78; 95% CI, 1.72-4.55; P < .001). The mean (SD) time to first relapse was significantly longer in the TAC group (323.99 [98.33] days) compared to the MMF group (263.21 [132.84] days). Furthermore, the TAC group showed a lower annual relapse rate than the MMF group (17.78% vs 41.48%) and required a significantly lower mean (SD) cumulative steroid dose (0.22 [0.10] mg/kg/day vs 0.34 [0.22] mg/kg/day). The safety profile was similar in both groups. In this randomized clinical trial, compared with MMF, a 1-year course of TAC therapy significantly extended the period of relapse-free survival in children with FRNS or SDNS. ClinicalTrials.gov Identifier: NCT04048161.

BackgroundManagement of patients with steroid-sensitive nephrotic syndrome (SSNS) is challenging because of frequent relapses. Causal variants in the human leukocyte antigen (HLA) class II region that are associated with relapse remain undetermined.MethodsWe collected a cohort of East Asian individuals comprising 206 pediatric patients with SSNS and 435 healthy controls from Southwest China. Ninety children with steroid-sensitive nephrotic syndrome without relapse (SSNSWR) and 116 children with steroid-dependent and/or frequent relapse nephrotic syndrome (SDNS/FRNS) were genotyped using Sanger sequencing. We then measured the transcriptional level, allele expression imbalance (AEI) and functional proteins of HLA-DQA1 and HLA-DQB1 in different stages of SDNS/FRNS.Resultsrs1464545187 in ANKRD36 was associated with an approximately 1.69-fold greater risk for SSNSWR (P = 0.04; 95% confidence interval [CI], 1.05–2.72). Clustered risk variants in HLA-DQA1 and HLA-DQB1 were significantly associated with SDNS/FRNS (rs1047989: P = 2.26E-07, odds ratio [OR] = 2.25, 1.65–3.05; rs9273471: P = 5.45E-05, OR = 1.84, 1.37–2.46; HLA-DQB1*06:02: P = 0.017, OR = 0.19, 0.04–0.77). The genotype distributions of rs1047989, 2:171713702, rs1049123, rs9273471, and HLA-DQB1*06:02 in patients with SSNS were significantly different from those in healthy controls. rs1047989 (HLA-DQA1) was significantly associated with a greater number of infections at relapse in SDNS/FRNS patients (P = 0.045, OR = 6.79, 95% CI: 1.29-168.52). Flow cytometry showed that the proportion of cells expressing HLA-DQA1+/DQB1+ (HLA-DQA1+, P = 0.0046; HLA-DQB1+, P = 0.0045) was lowest in the relapse stage. In addition, the mRNA levels of HLA-DQA1 and HLA-DQB1 were significantly greater in the relapse group than in the remission group (HLA-DQA1, P = 0.03; HLA-DQB1, P = 0.002). No significant AEIs were detected in the different stages of SDNS/FRNS. The rs1047989 variant is likely to affect the structure and stability of HLA-DQA1.Conclusionrs1464545187 is a risk locus for SSNSWR but not SDNS/FRNS in Chinese children. Functional variations in HLA-DQA1 and HLA-DQB1 are implicated in regulating the immune response of SSNS patients, which may explain the typical triggering of SDNS/FRNS onset by infections.