Back
Idiopathic nephrotic syndrome is the most common chronic glomerular disease in children. At least 30 % of children show frequent relapses and/or steroid dependence, defined as complicated frequently relapsing/steroid-dependent nephrotic syndrome (FRNS/SDNS). Approximately 10-15 % are resistant to steroids & 1-3 % to other steroid sparing regimens. The anti-CD20 monoclonal antibody rituximab (RTX) has been proposed as a rescue therapy for difficult-to-treat nephrotic syndrome. We conducted a clinical trial to evaluate the efficacy & safety of fixed versus on-demand RTX doses in difficult-to-treat SDNS/FRNS. RTX with a better safety profile can be the answer to the unmet need in this subset of cases.
Idiopathic CONS patients attending nephrology opd at a tertiary care centre were screened for SDNS & FRNS. Study duration was of 21/2 years. Among them,the maintenance group received 4 x 375 mg/m2 RTX at 1 week interval + 2 doses of RTX at 6th & 12th months respectively,who were compared with on-demand arm,receiving 4 doses of RTX as initial +2 doses after each treatment of relapse. Active infections,malignancy & CD 19< 0.5% were excluded. Low dose steroid was continued in the on-demand cohort. The primary endpoint was the increase in median time to first relapse & the cumulative relapse free period in maintenance over on-demand arm,failing at least one steroid sparing agent,mainly tacrolimus in our trial.
In the SDNS group,39 patients were there in maintenance arm vs 35 in on-demand arm. Mean time to remission after rituximab infusion was 3 months. Mean RTX doses in periodic arm was 6.3,way higher than 4.97 in rescue group. Total mean duration of remission was 14 months (maximum duration being 17 months) in maintenance arm vs 11 months in relapse arm.79.5% patients remaining in remission (62.5% in complete remission) were taken off steroids in the perioidic RTX therapy arm. Steroid load was 2.88 gm in on-demand group,much more than 1.15 gm in periodic arm.There was a significant increase in mean time to first relapse,13.8 months in maintenance vs 8.5 months in rescue group.
What we have successfully shown that with periodic therapy in maintenance arm, statistically significant time in remission was obtained, with increase in time to first relapse, along with a significant decrease in total steroid load but with a caveat that they required higher RTX doses. Remission was maintained without other immunosuppressants, especially corticosteroids, thus could prevent the plethora of side effects of prolonged steroid therapy. However, we cannot know for certain how long should we prolong the maintenance therapy. The study was conducted for approximately 30 months,which was not sufficient to find out the nature of adverse effects of rituximab,hence the risk of malignancy was not addressed adequately. Moreover the RTX doses were not coupled with repopulation of CD 19 cells in all the cases owing to financial constraints,but baseline IgG was done to rule out underlying hypogammaglobulinemia.This could open up a new way of formulating RTX doses in resource poor setup. What is the safe dose of rituximab will always remain a riddle at present, unless other long term studies are formulated.