Background: Long-term outcomes following multiple rituximab courses among children with frequently-relapsing, steroid-dependent nephrotic syndrome (FRSDNS) are unknown. Methods: A retrospective cohort study at 16 pediatric nephrology centers from 10 countries in Asia, Europe, and North America included children with FRSDNS who received ≥2 rituximab courses. Primary outcomes were relapse-free survival and adverse events. Results: 346 children (age 9.8 years, IQR 6.6-13.5; 73% boys) received 1149 rituximab courses. 145, 83, 50, 28, 22, and 18 children received 2, 3, 4, 5, 6 and ≥7 courses, respectively. Median follow-up was 5.9 years (IQR, 4.3-7.7). Relapse-free survival differed by treatment courses (clustered log-rank test p<0.001). Compared to the first course (10.0 months, 95% CI, 9.0-10.7), relapse-free period and relapse risk progressively improved following subsequent courses (12.0-16.0 months; HRadj, 0.03-0.13; 95% CI, 0.01-0.18; ps<0.001). B-cell depletion duration remained similar with repeated treatments (6.1 months, 95% CI, 6.0-6.3). Adverse events were mostly mild, most commonly hypogammaglobulinemia (50.9%), infection (4.5%), and neutropenia (3.7%). Side effects did not increase with more treatment courses nor higher cumulative dose. Only 78 of the 353 episodes of hypogammaglobulinemia were clinically significant. Younger age at presentation (2.8 vs 3.3 years; p=0.05) and at first rituximab (8.0 y vs 10.0 years; p=0.01) and history of steroid resistance (28% vs 18%; p=0.01) were associated with significant hypogammaglobulinemia. All 53 infective episodes resolved, except one patient with hepatitis B infection and another with EBV infection. There were 42 episodes of neutropenia, associated with history of steroid resistance (30% vs 20%, p=0.04). Upon last follow-up, 332 children (96%) had normal kidney function. Conclusion: Children receiving repeated rituximab for FRSDNS experience an improving clinical response. Side effects appear acceptable but significant complications can occur. These findings support repeated rituximab use in FRSDNS.

Children and young adults with steroid-dependent nephrotic syndrome (SDNS) are exposed to the toxic effects of both steroids and common steroid-sparing agents, such as calcineurin inhibitors, reporting an increased risk of kidney failure. 1 Alternative low-toxicity, long-acting therapies are needed to treat SDNS. 1 Methods | This randomized clinical trial was designed to test the superiority of a single dose of rituximab (375 mg/m 2 ) vs low-dose mycophenolate mofetil (MMF) (350 mg/m 2 twice daily) in preventing the recurrence of SDNS. Eligibility criteria were age 3 to 24 years and SDNS requiring prednisone 0.3 mg/kg/d to 1 mg/kg/d during at least 6 months before enrollment.Eligible White patients were randomly assigned in a 1:1 ratio to receive either rituximab (intervention) or oral MMF (active comparator) (Figure 1). Sex and age were equally distributed. The trial protocol (Supplement 1) and study were approved by the regional review board (Liguria, IT) and Italian Drugs Agency (AIFA) and the trial protocol was registered at ClinicalTrials.gov (NCT04402580). Written consent was obtained by patients or by their parents.The primary outcome was the occurrence of a relapse of SDNS within 12 months of randomization; the secondary outcome was the probability of remaining relapse-free up to 24 months from randomization. Relapse was defined by a urine protein/creatinine ratio (uPCR) of 2000 mg/g or more. Logistic regression was used to compare the risk of relapse at 1 year with a 2-sided P value of <.05 as statistical significance.

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Multicentric carpo-tarsal osteolysis (MCTO) is a rare osteolysis syndrome mainly involving carpal and tarsal bones usually presenting in early childhood. MCTO has autosomal dominant inheritance with heterozygous mutation in the MAFB gene. The skeletal disorder is often associated with chronic kidney disease. Data on clinical characterization and best treatment option of MCTO-associated nephropathy are scarce and mostly limited to case reports. With the aim to better define the phenotype and long-term outcomes of MCTO-associated nephropathy, we launched an online survey through the Workgroup for hereditary glomerulopathies of the European Rare Kidney Disease Network (ERKNet). Overall, we collected clinical and genetic data of 54 MCTO patients, of which 42 previously described and 12 new patients. We observed a high rate of kidney involvement (70%), early age of kidney disease onset, nephrotic-range proteinuria, and a kidney survival around of 40% at long-term follow-up. Our finding confirmed the heterogeneity of clinical manifestations and widen the spectrum of phenotypes resulting from MCTO-associated nephropathy. Furthermore, we report the first case of complete remission after treatment with cyclosporine A. We demonstrated that multidisciplinary care is essential for MCTO patients and early referral to nephrologists is therefore warranted to facilitate prompt treatment.