Introduction:Kidney outcomes in children with steroid-resistant nephrotic syndrome (SRNS) following rituximab remain unclear. Methods:We conducted an international retrospective cohort study across 23 centers in 17 countries, including children with SRNS who did not respond to calcineurin inhibitors (CNIs) and subsequently, received rituximab. Patients with genetic variants were excluded. The primary outcome was kidney survival. Results:We analyzed data on 151 children (53% males; median age at onset: 6.8 years; primary vs. secondary SRNS: 54% vs. 46%; focal segmental glomerulosclerosis [FSGS]: 62%). All subjects received CNIs before rituximab (0-3 months: 21%; 3-6 months: 26%; 6-12 months: 26%; > 12 months: 26%). Upon rituximab, 73 subjects (48%) had normal kidney function, 47 (31%) had chronic kidney disease (CKD)2, and 31 (21%) had CKD3. Twenty-eight (19%) developed kidney failure. Overall kidney survival was 82.7%, 75.8%, and 72.3% at 3, 5, and 7 years post-rituximab. Baseline CKD staging before rituximab was associated with kidney survival at 5 years (log-rank P < 0.001); CKD stage 1, 91.7%; CKD stage 2, 70.4%; and CKD stage 3, 35.5%). The predictive factors for inferior kidney survival were CKD2 (adjusted hazard ratio [HRadj]: 2.7, 95% confidence interval [CI]: 1.5-4.9, P < 0.001), lower baseline serum albumin (log-rank P = 0.01; HRadj: 0.88, 95% CI: 0.81-0.95; P < 0.001) and FSGS (log-rank P = 0.03; HRadj: 3.4, 95% CI: 1.1-10.0; P < 0.001). Nonremission at 6 months was associated with inferior kidney survival (61.2% at 5 years), compared with complete remission (CR) or partial remission (PR) (100% at 5 years) (log-rank P = 0.01; HRadj: 14.1, 95% CI: 2.2-93.5, P = 0.01). Duration of prior calcineurin inhibition and SRNS type were not significant predictors. Conclusion:Kidney survival of SRNS following add-on rituximab is 70% to 80% over 3 to 7 years. Nonresponse, preexisting CKD, lower albumin, and FSGS predict inferior kidney survivals.

Introduction: The efficacy and safety of rituximab in children aged < 6 years with frequently-relapsing and/or steroid-dependent nephrotic syndrome (FRSDNS) remain controversial. Methods: We conducted a retrospective cohort study at 16 pediatric nephrology centers from 10 countries in Asia, Europe, and North America. We first analyzed young children with FRSDNS who received their first rituximab treatment before the age of 6 years. As a secondary analysis, we matched young children aged < 6 years with older patients who received their first rituximab between the ages of 6 to 21 years. Results: One hundred one children (70 boys) received their first rituximab courses at the age of 4.5 (interquartile range [IQR]: 3.6-5.4) years, with an observation period of 4.6 (IQR: 3.2-6.6) years. Most children were Europeans (42%) and Southeast Asians (35%). Seventy-five children (74%) were multidrug dependent. In the primary analysis, among the 101 young children, the median relapse-free survival after the first rituximab treatment was 8.8 (95% confidence interval [CI]: 7.5-11.0) months by Kaplan-Meier analysis. Each additional month of concurrent immunosuppression post-rituximab reduced relapse risk by 8% (adjusted hazard ratio: 0.92; 95% CI: 0.89-0.96; P < 0.001). Increasing age at rituximab administration trended toward a lower relapse risk (adjusted hazard ratio: 0.76/yr; 95% CI: 0.57-1.03; P = 0.07). The annual relapse rate reduced from 3 (IQR: 2-4) to 1 (IQR: 0-1) following rituximab (P < 0.0001). Rituximab was repeated in 85 children (84%), mostly because of relapses. The leading adverse events were hypogammaglobulinemia (n = 30/53, 57%), neutropenia (n = 9/97, 9%), and infection (n = 8/115, 8%). Baseline low IgG levels were associated with hypogammaglobulinemia post-rituximab. All children except 1 had normal kidney function at the last follow-up. In the secondary analysis (70 young vs. 70 older children), although insignificant, younger children showed a trend toward earlier relapse (8.3 vs. 11.3 months; log-rank test P = 0.14), and more complications (hypogammaglobulinemia, 63% vs. 35%; P = 0.01; neutropenia, 13% vs. 7%; infection, 9% vs. 4%). Conclusion: Rituximab offers reasonable efficacy in young children with FRSDNS, with a trend toward a shorter relapse-free period and more potential complications. Rituximab should be reserved until established treatments are exhausted.

The pathogenesis of primary focal segmental glomerulosclerosis (FSGS) is incompletely understood, and outcomes remain poor. Some patients respond to Rituximab, especially patients who have hyporesponsive T-cells, but the underlying mechanism is unknown. This study aimed to investigate the association between B-cell activation and T-cell hypo-responsiveness as well as Rituximab response. A cohort of 33 patients with childhood-onset FSGS receiving Rituximab were recruited. T-cell hypo-responsiveness was defined as stimulated T-cell IFNγ <2.5%, and B-cell activation was characterized by CD80 expression and cytokine production. T-cell hypo-responsiveness was associated with Rituximab response (OR: 5.4 (95% CI: 1.2-25), p=0.028). Compared to T-cell normo-responsive patients, T-cell hypo-responsive patients had elevated activated CD19+CD80+ B-cells (16% (IQR 6-25) vs 5% (IQR: 1-9), p=0.009), and upregulation in resting B-cell cytokine production (15/27 cytokines, p<0.05). Rituximab selectively restored T-cell responsiveness and abolished elevated B-cell CD80 expression and resting cytokine production in these patients, although nascent B-cell activation could still be detected on in vitro stimulation (6/27 cytokines, p<0.05). Resting B-cell culture supernatants from patients with hypo-responsive T-cells (p=0.02) but not normo-responsive T-cells were able to induce cytoskeletal rearrangements in cultured podocytes. Together with T-cell responsiveness, resting B-cell cytokine production was able to strongly predict Rituximab response (AUC 0.922±0.077, p=0.002), and also the duration of Rituximab response (AUC 0.958±0.062, p=0.019). Rituximab response in childhood-onset FSGS occurs in a subgroup of patients with B-cell mediated disease characterized by B-cell activation and the production of podocyte damaging factors. Resting B-cell cytokine production can predict Rituximab response, and if it will be long-lasting.

1. KTP-NUCMI, National University Hospital, Singapore 2. Myanmar Paediatric Society, Myanmar 3. National University Singapore - Kent Ridge Campus: National University of Singapore

The efficacy and safety of rituximab in childhood steroid-resistant nephrotic syndrome (SRNS) remains unclear. Therefore, we conducted a retrospective cohort study at 28 pediatric nephrology centers from 19 countries in Asia, Europe, North America and Oceania to evaluate this. Children with SRNS treated with rituximab were analyzed according to the duration of calcineurin inhibitors (CNIs) treatment before rituximab [6 months or more (CNI-resistant) and under 6 months]. Primary outcome was complete/partial remission (CR/PR) as defined by IPNA/KDIGO guidelines. Secondary outcomes included kidney failure and adverse events. Two-hundred-forty-six children (mean age, 6.9 years; 136 boys; 57% focal segmental glomerulosclerosis, FSGS) were followed a median of 32.4 months after rituximab. All patients were in non-remission before rituximab. (146 and 100 children received CNIs for 6 month or more or under 6 months before rituximab, respectively). In patients with CNI-resistant SRNS, the remission rates (CR/PR) at 3-, 6-, 12- and 24-months were 26% (95% confidence interval 19.3-34.1), 35.6% (28.0-44.0), 35.1% (27.2-43.8) and 39.1% (29.2-49.9), respectively. Twenty-five patients were in PR at 12-months, of which 22 had over 50% reduction in proteinuria from baseline. The remission rates among children treated with CNIs under 6 months before rituximab were 42% (32.3-52.3), 52% (41.8-62.0), 54% (44.3-64.5) and 60% (47.6-71.3) at 3-, 6-, 12-, and 24-months. Upon Kaplan-Meier analysis, non-remission and PR at 12-months after rituximab, compared to CR, were associated with significantly worse kidney survival. Adverse events occurred in 30.5% and most were mild. Thus, rituximab enhances remission in a subset of children with SRNS, is generally safe and CR following rituximab is associated with favorable kidney outcome.

Dear Editor, In a representative cohort of immunocompromised young people, we observed marked differences in humoral and cellular responses to a standard two-dose mRNA vaccination regime between disease categories. These differences are only partially explained by prevailing immunosuppression, which highlights the limitations of the current approach in selecting young patients for additional vaccine doses based primarily on the use of immunosuppressive medication. Immunocompromised adults are recommended to receive a third primary dose of SARS-CoV-2 mRNA vaccines to promote seroconversion, and more recently a second booster dose.1,2 There is, however, a paucity of vaccine response data from immunocompromised young people to justify this approach. We characterised the humoral and cellular responses to a standard two-dose regime of SARS-CoV-2 mRNA vaccines in a single-centre cohort of immunocompromised young people with a representative range of medical conditions and subsequently identified risk factors for an attenuated response. A total of 97 immunocompromised patients and 22 controls were prospectively recruited. Six participants did not complete the study (Figure S1) and were excluded. The immunocompromised cohort included patients with inflammatory bowel disease (IBD), kidney transplant (KTX), liver transplant (LTX), idiopathic nephrotic syndrome (INS), kidney failure (ESKD), IgA nephropathy/vasculitis (IGA), juvenile idiopathic arthritis (JIA), systemic lupus erythematosus (SLE) and idiopathic uveitis (UVI). Baseline characteristics (Table 1, Figure 1A) were comparable between controls and the immunocompromised cohort, and disease groups were homogenous in terms of age and dose interval (p > .05) which have been reported to affect antibody titres. Following vaccination, only 68 (73%) patients had antispike (Anti-S) protein titres >250 U/ml, compared to 20 (100%) controls (p = .006) (Table 1, Figure 1B). Similarly,

Long-term humoral immunity is mediated by short-lived plasma cells (replenished by memory B cells) and long-lived plasma cells. Their relative contributions are uncertain for immunity to SARS-CoV-2, especially given the widespread use of novel mRNA vaccines. Yet, this has far-reaching implications in terms of the need for regular booster doses in the general population and perhaps even revaccination in patients receiving B cell-depleting therapy. We aimed to characterise anti-SARS-CoV-2 antibody titres in patients receiving Rituximab following previous SARS-CoV-2 vaccination. We recruited 10 fully vaccinated patients (age: 16.9 ± 2.52 years) with childhood-onset nephrotic syndrome, not in relapse, receiving Rituximab for their steroid/calcineurin-inhibitor sparing effect. Antibodies to SARS-CoV-2 spike (S) and nucleocapsid (N) proteins were measured immediately prior to Rituximab and again ~6 months later, using the Roche Elecys® Anti-SARS-CoV-2 (S) assay. All ten patients were positive for anti-S antibodies prior to Rituximab, with six patients (60%) having titres above the upper limit of detection (>12,500 U/mL). Following Rituximab therapy, there was a reduction in anti-S titres (p = 0.043), but all patients remained positive for anti-S antibodies, with five patients (50%) continuing to have titres >12,500 U/mL. Six patients (60%) were positive for anti-N antibodies prior to Rituximab. Following Rituximab therapy, only three of these six patients remained positive for anti-N antibodies (p = 0.036 compared to anti-S seroreversion). Humoral immunity to SARS-CoV-2 is likely to be mediated in part by long-lived plasma cells.

Children with lupus have a higher chance of nephritis and worse kidney outcome than adult patients. We retrospectively analyzed clinical presentation, treatment and 24-month kidney outcome in a cohort of 382 patients (≤ 18 years old) with lupus nephritis (LN) class ≥ III diagnosed and treated in the last 10 years in 23 international centers. The mean age at onset was 11 years 9 months and 72.8