Systematic Review and Meta-Analysis of Rituximab for Steroid-Dependent or Frequently Relapsing Nephrotic Syndrome in Children

Objective: To explore the effectiveness and safety of rituximab (RTX) for steroid-dependent or frequently relapsing nephrotic syndrome via a systematic review and meta-analysis.Methods: All the literature about RTX therapy for childhood nephrotic syndrome (NS) on PubMed, Web of Science, Cochrane Library, EMBASE, and Chinese biomedical literature database published before November 1, 2019, were conducted and selected according to the preset criteria. The Cochrane bias risk assessment tool was used to evaluate the quality of the literature included. The outcome data were analyzed by RevMan 5.3 software.Results: There were six RCT studies that met the inclusion criteria with a moderate quality after evaluation. At the end of the treatment, the relapse rate of NS in the RTX group reduced significantly when compared with that in the control group [odds ratio (OR) = 0.11, 95% confidence interval (CI) (0.03, 0.43), p = 0.001]. The number of patients in the RTX group used less steroid or/and calcineurin inhibitors significantly than that in the control group [OR = 0.05, 95% CI (0.01, 0.28), p = 0.0007]. For children who were steroid-dependent, RTX treatment significantly reduced the dosage of the steroid, compared with that in control [standardized mean difference (SMD) = −1.49, 95% CI (−2.00, −0.99), p < 0.00001]. There was no significant reduction in protein excretion between the two groups [SMD = −0.33, 95% CI (−0.71, 0.04), p = 0.08]. Fewer serious adverse reactions of RTX in the six studies were reported and most adverse events were mild.Conclusion: RTX is effective and safe for children with steroid-dependent or frequently relapsing nephrotic syndrome.Systematic Review Registration: Identifier: CRD 42020150933. https://www.crd.york.ac.uk/prospero/. This review has been registered to the PROSPERO on 27 Feb 2020.

Mycophenolate Mofetil in the Treatment of Steroid-Dependent or Frequently Relapsing Nephrotic Syndrome in Children: A Meta-Analysis

Objectives: This meta-analysis aims to evaluate the efficacy and safety of the mycophenolate mofetil (MMF) in the treatment of steroid-dependent nephrotic syndrome (SDNS) or frequently relapsing nephrotic syndrome (FRNS) in children.Methods: We searched for the studies especially the randomized controlled trials in PubMed, Cochrane Library, Embase, China National Knowledge Infrastructure, and Wan Fang database. The data were analyzed by Review Manager 5.3 software. We used the GRADE pro-Guideline Development Tool online software to evaluate the quality of evidence.Results: Finally, we identified 620 studies, of which we included five randomized controlled trials and one prospective cohort study with 447 children. The results showed the following: (1) the relapse-free survival rate within 1 year—the MMF group was superior to the levamisole group [ratio difference (RD) = 0.13, 95% CI (0.02, 0.24), P = 0.02] but not to the calcineurin inhibitors (CNIs) group [RD = −0.27, 95%CI (−0.40, −0.14), P < 0.0001]; (2) the number of relapses within 1 year—the MMF group was less than that in the CNIs and levamisole group [mean difference (MD) = −0.26, 95%CI (−0.45, −0.08), P = 0.005]; (3) the cumulative prednisone dosage—the MMF group was lower than that in the control group [standardized mean difference (SMD) = −0.32, 95%CI (−0.53, −0.11), P = 0.003]; (4) incidence of adverse reactions—there was no significant difference between the MMF group and the control group [RD = 0.02, 95%CI (−0.04, 0.09), P = 0.46].Conclusion: The therapy of mycophenolate mofetil in the treatment of SDNS or FRNS in children has a certain advantage in reducing the number of relapses and cumulative prednisone dosage within 1 year when compared with the CNIs and levamisole. However, due to the limited quantity and quality of the included studies, the conclusions above need to be confirmed by more high-quality randomized controlled trials.

Rhabdomyosarcoma in a child with nephrotic syndrome treated with cyclosporine: a case report with literature review

Background In patients with frequently relapsing nephrotic syndrome, immunosuppressive therapy such as cyclosporine are often required to maintain remission. Cyclosporine has been noted to have tumorgenesis effects. In this case report, we present a child with relapsing nephrotic syndrom developed a rhabdomyosarcoma on her tongue after adout 4 years of continual immunosuppressive therapy. Case presentation A 2-year-old female child had nephrotic syndrome (urine protein-creatinine ratio 749.1 mg/mg; blood urea nitrogen 11 mg/dL; serum creatinine 0.3 mg/dL; and serum albumin 1.8 g/dL.) Proteinuria resolved on treatment with daily prednisolone for 4 weeks at the dose of 45 mg (2.5 mg/kg/day) but recurred with taper from 25 mg/day to 10 mg/day. At least five more episodes of relapse occurred within about a 3-year period. After the third relapse, she was treated with prednisolone and cyclosporine (at initial dose of 50 mg/day [1.7 mg/kg/day]) for immunosuppression. About 4 years after the diagnosis of nephrotic syndrome had been made, an embryonal rhabdomyosarcoma developed on her tongue. The cancer was treated with TPOG-RMS-LR protocol, with vincristine, actinomycin, and cyclophosphamide. Magnetic resonance imaging scan, performed about 3 years after the start of TPOG-RMS-LR therapy, revealed complete remission of the cancer. Conclusions Although treatment with cyclosporine cannot be conclusively implicated as the cause the rhabdomyosarcoma in this patient, the association should prompt consideration of its use in the treatment of frequently relapsing nephrotic syndrome in children.

Efficacy and safety of intravenous immunoglobulin with rituximab versus rituximab alone in childhood-onset steroid-dependent and frequently relapsing nephrotic syndrome: protocol for a multicentre randomised controlled trial

IntroductionGuidelines for the treatment of steroid-dependent nephrotic syndrome (SDNS) and frequently relapsing nephrotic syndrome (FRNS) are lacking. Given the substantial impact of SDNS/FRNS on quality of life, strategies aiming to provide long-term remission while minimising treatment side effects are needed. Several studies confirm that rituximab is effective in preventing early relapses in SDNS/FRNS; however, the long-term relapse rate remains high (~70% at 2 years). This trial will assess the association of intravenous immunoglobulins (IVIgs) to rituximab in patients with SDNS/FRNS and inform clinicians on whether IVIg’s immunomodulatory properties can alter the course of the disease and reduce the use of immunosuppressive drugs and their side effects.Methods and analysisWe conduct an open-label multicentre, randomised, parallel group in a 1:1 ratio, controlled, superiority trial to assess the safety and efficacy of a single infusion of rituximab followed by IVIg compared with rituximab alone in childhood-onset FRNS/SDNS. The primary outcome is the occurrence of first relapse within 24 months. Patients are allocated to receive either rituximab alone (375 mg/m²) or rituximab followed by IVIg, which includes an initial Ig dose of 2 g/kg, followed by 1.5 g/kg injections once a month for the following 5 months (maximum dose: 100 g).Ethics and disseminationThe study has been approved by the ethics committee (Comité de Protection des Personnes) of Ouest I and authorised by the French drug regulatory agency (Agence Nationale de Sécurité du Médicament et des Produits de Santé). Results of the primary study and the secondary aims will be disseminated through peer-reviewed publications.Trial registration numberNCT03560011.