The use of rituximab in childhood steroid-resistant nephrotic syndrome: an international, multi-centre study

t is controversial whether rituximab induces remission in childhood idiopathic steroid-resistant nephrotic syndrome (SRNS) and which patient subgroups benefit most from the therapy.

We conducted a retrospective cohort study at 28 paediatric nephrology centres from 19 countries in Asia, Europe, North America and Oceania. Children with SRNS unresponsive to corticosteroids and calcineurin inhibitors were included, and were stratified into two groups: use of calcineurin inhibitors (CNIs) < or >=6 months prior to rituximab administration. Primary outcome was complete or partial remission (CR/PR), defined by IPNA SRNS guidelines, at 3-, 6- and 12-month post-rituximab. Secondary outcomes included kidney survivals.

246 children (age, 6.9±4.2 years; 55% boys) were included, of which 112 and 134 patients presented with initial and late SR. The commonest histological diagnosis was focal segmental glomerulosclerosis (FSGS; n=136, 57%), followed by minimal change disease (n=79, 33%). 146 and 100 children received CNIs for more than and less than 6 months prior to rituximab administration, respectively.

All patients were non-remission (serum albumin <30g/L) prior to rituximab, and proteinuria were in nephrotic- and subnephrotic-range in 86% and 14% patients. The median eGFR was 93 ml/min/1.73m2 (IQR, 66-126.3) and urine protein/creatinine ratio was 3.2mg/mg (IQR, 2.9-7.6). Majority of patients received rituximab at 750mg/m2 (n=114, 46.3%) and 1500mg/m2 (n=100, 40.7%). 99.2% patients achieved B-cell depletion. Median follow-up from rituximab administration was 32.4 (IQR, 18.6-64.9) months.

Overall, 32.5% patients attained CR/PR (19.9%/16.6%) at 3-month, which significantly increased to 42.3% at 6-month (CR/PR, 23.2%/19.1%; p<0.001) and remained similar at 12-month (43.3%; CR/PR, 24%/19.3%). Patients who failed to respond following >=6 months had a significantly lower remission rates at 6- (35.6% vs 52%, p<0.001) and 12-month (35.1% vs 54.5%), compared to those who were treated with CNIs for <6 months.

Among patients who received CNIs >=6 months prior to rituximab, multivariable analysis demonstrated that subnephrotic-range proteinuria at the time of rituximab (ORadj 5.58, 95%CI 1.07-37.06, p=0.049) and late SR (ORadj 2.55, 95%CI 1.09-6.15, p=0.03) were favourable predictive factors for attaining CR/PR following rituximab. In contrast, patients with advanced chronic kidney disease stage 3 or above were at risk of non-remission (ORadj 0.06, 95%CI 0.00-0.33, p=0.008). Rituximab dose, concurrent immunosuppression and additional rituximab did not impact on disease remission. There was no predictive factor identified in the patients treated with CNIs <6 months before rituximab.

Non-remission at 6- and 12-month were associated with poor kidney survival (Fig 1; log rank p<0.001). Upon cox regression, non-response to rituximab at 6-month (HRadj 6.95, 95%CI 2.22-21.76, p<0.001), pre-existing chronic kidney disease stage 2 or above (HRadj 2.4, 95%CI 1.04-5.57, p=0.04), and a histology of FSGS (HRadj 4.3, 95%CI 1.4-13.23, p=0.01) were significant predictors for kidney failure and/or death. Most adverse events were mild.

Rituximab therapy may induce remission in a subset of children with SRNS. Late SR and subnephrotic-range proteinuria are favourable predictive factors for response In children who failed to respond to prednisolone and ³6 months of CNIs, and are potential subgroup of patients who may benefit from rituximab therapy.