Randomized clinical trial to compare efficacy and safety of repeated courses of rituximab to single-course rituximab followed by maintenance mycophenolate-mofetil in children with steroid dependent nephrotic syndrome

Abstract

Background Approximately 30% of children with idiopathic nephrotic syndrome develop a complicated course with frequent relapses or steroid dependency. Rituximab, a B cell depleting monoclonal antibody, is a safe and effective alternative to steroids or other immunosuppressants for achieving and maintaining remission in this population at short term. Despite the good initial response relapses inevitably occur after regeneration of B lymphocytes, necessitating either repeat courses of rituximab or addition of another steroid-sparing immunosuppressant. Methods This is a prospective, single-center, open-label, two-parallel-arm randomized controlled phase III study among children with steroid dependent nephrotic syndrome who are maintained in remission with oral steroids. One hundred children will be randomized to either Rituximab and maintenance Mycophenolate mofetil (A) or repeated courses of prophylactic Rituximab only (B). In arm A, mycophenolate mofetil (1200 mg/m2 per day) will be started 3 months after Rituximab administration. In arm B, Rituximab infusions will be administered at 0, 8 and 16 months if B cell count normalize at the given time points. Prednisolone will be discontinued in both groups 2 weeks following first course of rituximab. Primary aim is to evaluate the difference in 24-month relapse-free survival. Main secondary endpoints are cumulative prednisolone dose, frequency of relapses and changes in anthropometry. Circulating B lymphocyte populations will be studied as biomarkers or predictors of rituximab responsiveness and adverse events will be analysed. Discussion The study will provide evidence as to the comparative safety and efficacy of two alternative steroid-sparing therapeutic options in children suffering from steroid dependent nephrotic syndrome. The two-year study design will address the long-term results obtained with the alternative treatment protocols. Trial registration This trial was prospectively registered to the Clinicaltrial.gov (NCT03899103 dated 02/04/2019; https://clinicaltrials.gov/) and Clinical Trials Registry of India (CTRI/2019/04/018517 dated 09/04/2019).

Proteomic profile of mesothelial exosomes isolated from peritoneal dialysis effluent of children with focal segmental glomerulosclerosis

“…TGFβ1 plays a central role in fibrosis and EMT also in PD patients 16 , 17 . Increasing evidence from a number of studies suggest to reduce the use of CNIs, due to their nephrotoxicity 18 , 19 . We believe that new insights on CNIs toxicity/ pro-fibrotic role in PD could contribute to increase the shift toward different therapeutic approaches, also as first line therapy.…”

Long-Term Efficacy and Safety of Rituximab Versus Tacrolimus in Children With Steroid Dependent Nephrotic Syndrome

“…Ongoing clinical trials such as RITURNS-II, which compares repeated rituximab monotherapy with single dosing followed by MMF maintenance therapy, are expected to deliver further insight into the most efficacious, safe, and cost effective use of B-cell depleting agents in childhood idiopathic nephrotic syndrome. 25 …”

B-cell activating factor (BAFF) and its receptors’ expression in pediatric nephrotic syndrome is associated with worse prognosis

“…The cause of idiopathic NS remains unknown, but the immune role of B and T cells in the pathogenesis of this condition has been suggested. Although depleting B cells with rituximab (anti-CD-20 therapy) is an effective treatment in patients with a complicated disease [10], the mechanisms involving B cells in patients with NS are not well described. In addition, the role of BAFF (an important cytokine associated with B-cell survival and autoimmunity) has not been studied in pediatric patients with NS.…”

“…For instance, T cells may produce cytokines that affect glomeruli and cause increased permeability, as well as the production of circulating factors that alter podocyte structure and functions, resulting in proteinuria [9]. On the other hand, B-cell involvement is also suggested based on remission after treatment with B-cell-depleting therapies, such as rituximab [10].…”