Nephrotic syndrome (NS) is the most frequent chronic glomerular disease in the paediatric population. It is defined as glomerular disease with urinary protein excretion greater than 40 mg/m2/h, low serum albumin levels under 2.5 g/dL and oedema. The incidence of NS is of 2–7 new cases per 100 000 children per year, with a higher prevalence (15 cases per 100 000 children) on account of the protracted course of disease. It is more frequent in boys (2:1) and usually has onset between ages 2 and 8 years, with an incidence peak between 3 and 5 years. Idiopathic NS amounts to 90% of cases of NS in children, and minimal change disease (MCD) is the most frequent histological type, followed by focal segmental glomerulosclerosis (FSGS).

Steroid therapy is the cornerstone of NS treatment. Most children respond to this approach, although 20% develop resistance to steroids at some point in the course of disease. About 50% of patients with steroid-sensitive NS have frequent relapses (more than 2 relapses in the first 6 months or more than 3 at any time in the course of disease), of who approximately 50%–60% experience relapses during steroid therapy or soon after achieving remission, which is known as steroid-dependent NS.

Immunosuppressive agents, such as cyclophosphamide, chlorambucil, levamisole, mycophenolate mofetil, cyclosporin A and/or tacrolimus may be used to attempt to reduce or eliminate steroid therapy, although there is no consensus on the selection, duration and sequence of these second-line drugs. In 2004, evidence was first published suggesting that rituximab (RTX), a chimeric anti-CD20 monoclonal antibody that inhibits CD20+ B cell proliferation and differentiation, could be beneficial for treatment of NS. The mechanisms of action of RTX in NS are not well understood, but in addition to B cells, RTX may also act on targets found in T cells, inflammatory cytokines and even podocytes.1

Since 2004, different studies have produced promising evidence on the role of this antibody in patients with difficult-to-treat NS, although its specific indications, appropriate dosage and schedule or long-term adverse effects have yet to be established. We present our experience with patients treated with RTX in recent years with the aim of contributing information that may help define the role of RTX in the management of steroid-dependent idiopathic NS.

We conducted a retrospective study in patients with steroid-dependent idiopathic NS managed in the Section of Paediatric Nephrology of a tertiary care hospital in Spain that received at least one cycle of RTX at any point in the course of disease.

Evidence from recent studies show that treatment with RTX is effective in children with difficult-to-treat N, both in terms of the frequency of relapses and its steroid- and immunosuppressant-sparing effect. Although the methodological limitations of our study should be taken into account (retrospective design), our findings in patients treated with RTX seem to confirm it.

On one hand, we found a marked reduction in the frequency of relapses after treatment with RTX, which declined from 3.6 relapses/year in the year preceding the first cycle of RTX to 0.1 relapses/year in the first year post RTX (during which 7 of the 8 patients in the study were free of relapses). These benefits of RTX in the management of NS have been described repeatedly in recent years,7–16 and some authors have even proposed using RTX as a first-line drug for treatment of steroid-dependent NS,17–19 based on the comparison of its efficacy with the efficacy of other immunosuppressant agents used habitually for management of this disease. A multicentre, double-blind, randomized and placebo-controlled trial is currently underway to assess the efficacy and safety of RTX for treatment of childhood-onset, early-stage uncomplicated frequently-relapsing or steroid-dependent NS in patients that have not previously received other immunosuppressant drugs.20

On the other hand, treatment with RTX allowed a reduction in the use of other immunosuppressant drugs; only steroids were used after initiation of RTX, and there was a 96.5% reduction in the steroid dose in the last 3 months of follow-up. These outcomes were similar to those reported by other authors8 and are particularly relevant if we take into account their use in patients with difficult-to-treat NS, who in most cases are refractory to multiple first- and second-line treatments.

Since the use for treatment of NS is not included in the summary of product characteristics of RTX, the exact indications and optimal dosage for this purpose have yet to be established, and the dose per cycle, interval between cycles and total number of cycles vary widely between published sources. Our patients were treated with a standard dose of RTX of 375 mg/m2 (body surface area) and, with the exception of a patient that received 4 weekly doses in one cycle, received 1–2 weekly doses per cycle in the schedule used most frequently by other authors.8,20 This regimen could be a valid and effective option to use from the beginning, as opposed to daily doses of other immunosuppressants, in cases in which there are concerns about adherence.

Several studies4,21–23 have found a direct association between the number of doses of RTX, the duration of B cell depletion and the decrease in the risk of relapse. This trend, which was also found in our patients, has led to specific recommendations regarding the immediate administration of additional doses of RTX once there is evidence of B cell recovery without awaiting a relapse,24 although this is not currently widespread practice. At the same time, another clinical phenomenon that has been described in relation to treatment of NS with RTX is a tendency toward earlier B cell recovery associated with younger age,4 which our findings seem to corroborate. Last of all, our findings also corroborate the positive corelation between the age at initiation of RTX and the duration of B cell depletion (and therefore of relapse-free periods) described in previous studies.4,11

Still, the association between B cell recovery and the recurrence of disease in our patients was not categorical, as there was a significant gap between both events (more than seven months). This suggests that RTX has mechanisms of action that are not directly dependent on the B cell count, something that has been described previously.25–27 In our series, additional doses of RTX were not administered in isolation based solely on the biological marker of B cell recovery, and the occurrence of a new relapse, following evidence of B cell recovery, was the clinical situation that prompted prescription of an additional cycle of RTX. Other biological markers (such as changes in T cell subsets) may be useful in the management of patients with NS managed with RTX.27

Several studies have found an increase in the effectiveness of RTX when combined with mycophenolate mofetil,4–6 something that is also suggested by our results, despite the small number of patients. Recently, Takahashi et al.7 found similar results with the use of mizobirine (a purine inhibitor) pulse therapy following treatment with RTX. At present, this is not widespread practice in nephrology, and its indication has yet to be properly established.

By the end of the post-RTX follow-up period (median, 46.5 months; range, 5–97), there had been no evidence of significant adverse events attributable to RTX in our patients, infectious or otherwise. Needless to say, the relevance of this outcome and the inferences we can make about potential long-term implications are limited by the small number of patients included in the study and the duration of follow-up.8,11,28,29

In conclusion, RTX achieved favourable outcomes in our series of paediatric patients with steroid-dependent NS, corroborating its efficacy and supporting its consideration as an appropriate pharmacological agent for use in difficult-to-treat cases. Although we did not observe adverse events or manifest infectious complications associated with treatment with RTX in the short term, adequate studies are nevertheless required to establish the optimal regimen (dosage, interval between and total number of cycles), the clinical impact and the potential adverse effects of RTX in the long term.

This research did not receive any external funding.

The authors have no conflicts of interest to declare.