Rituximab in steroid-dependent or frequently relapsing idiopathic nephrotic syndrome

Abstract

The outcome of steroid-dependent or frequently relapsing nephrotic syndrome of minimal change disease (MCD), mesangial proliferative GN (MesGN), or FSGS may be poor and with major treatment toxicity. This academic, multicenter, off-on trial (ClinicalTrials.gov #NCT00981838) primarily evaluated the effects of rituximab therapy followed by immunosuppression withdrawal on disease recurrence in 10 children and 20 adults with MCD/MesGN (n=22) or FSGS who had suffered ≥2 recurrences over the previous year and were in steroid-induced remission for ≥1 month. Participants received one dose (n=28) or two doses of rituximab (375 mg/m(2) intravenously). At 1 year, all patients were in remission: 18 were treatment-free and 15 never relapsed. Compared with the year before rituximab treatment, total relapses decreased from 88 to 22 and the per-patient median number of relapses decreased from 2.5 (interquartile range [IQR], 2-4) to 0.5 (IQR, 0-1; P<0.001) during 1 year of follow-up. Reduction was significant across subgroups (children, adults, MCD/MesGN, and FSGS; P<0.01). After rituximab, the per-patient steroid maintenance median dose decreased from 0.27 mg/kg (IQR, 0.19-0.60) to 0 mg/kg (IQR, 0-0.23) (P<0.001), and the median cumulative dose to achieve relapse remission decreased from 19.5 mg/kg (IQR, 13.0-29.2) to 0.5 mg/kg (IQR, 0-9.4) (P<0.001). Furthermore, the mean estimated GFR increased from 111.3±25.7 to 121.8±29.2 ml/min per 1.73 m(2) (P=0.01), with the largest increases in children and in FSGS subgroups. The mean height z score slope stabilized in children (P<0.01). Treatment was well tolerated. Rituximab effectively and safely prevented recurrences and reduced the need for immunosuppression in steroid-dependent or frequently relapsing nephrotic syndrome, and halted disease-associated growth deficit in children.

Figures

Figure 1.

Study flow chart. Of 44 screened patients, 32 fulfill the selection criteria and 30 consent to study participation. Of them, 14 never relapse despite completed withdrawal of steroid and any other immunosuppressant.

Figure 2.

Box plot of the number of NS relapses over 1 year of follow-up after rituximab administration, and during the year before rituximab administration in the study group as a whole (overall), and in different age (children versus adults) and diagnosis (MCD/MesGN versus FSGS) subgroups considered separately.

Figure 3.

Time to NS relapse was similar between age and diagnosis groups. Kaplan–Meier curves showing the proportion of participants progressing to the first NS relapse at different time points over 1 year of follow-up after rituximab administration in the study group as a whole (overall, upper panel) and in different age (children versus adults) and diagnosis (MCD/MesGN versus FSGS) subgroups considered separately (middle and lower panels, respectively). 95% CI, 95% confidence interval; HR, hazard ratio.

Figure 4.

Circulating B cells at the time of rituximab administration (day 0) and at different time points thereafter in participants with or without relapses of NS throughout the 1-year observation period. Up to day 210, B-cell counts are always significantly lower compared with baseline in both groups. From day 240 to day 365 differences were still significant versus baseline in nonrelapsers, but were no longer significant in relapsers.

Figure 5.

Rituximab reduced the need for maintenance immunosuppression. Numbers of patients with any maintenance immunosuppressive therapy (left), or on maintenance therapy with steroid alone (middle), or steroid plus one or two additional immunosuppressive medications (right) at the time of rituximab administration (baseline) and at 1 year after treatment administration.

Figure 6.

Rituximab allowed to significantly reduce the steroid therapy doses. Box plot of per-patient daily steroid maintenance dose administered to prevent NS recurrences at the time of rituximab administration (baseline) and at 1 year after treatment administration (left), and cumulative steroid dose administered to treat all NS recurrences (middle) and each single NS recurrence (right) observed over 1 year of follow-up after rituximab administration and during the year before rituximab administration. All data are adjusted for patient body weight.

Figure 7.

Reduction or withdrawal of steroids after rituximab therapy blunted the increasing growth deficit previously observed in children over 3-year steroid exposure and normalized their growth rate up to the 3-year follow-up. Height z scores (left) and mean height z score slope (right) during the two 3-year observation periods before and after rituximab administration in the 10 children with steroid-dependent NS. *P<0.05 versus month 0; **P<0.01 versus month 0; ○P <0.05 versus −12 months.