Rituximab in combination with cyclosporine and steroid pulse therapy for childhood-onset multidrug-resistant nephrotic syndrome: a multicenter single-arm clinical trial (JSKDC11 trial)

Abstract

Background: Only 80% of children with idiopathic nephrotic syndrome respond well to glucocorticoid therapy. Multidrug-resistant nephrotic syndrome (MRNS) is associated with a poor kidney prognosis. Several retrospective studies have identified rituximab as an effective treatment for MRNS; however, prospective studies are required to assess its efficacy and safety.

Methods: We conducted a multicenter, non-blinded, single-arm trial to investigate the efficacy and safety of rituximab in patients with childhood-onset MRNS who were resistant to cyclosporine and more than three courses of steroid pulse therapy. The enrolled patients received four 375 mg/m² doses of rituximab in combination with baseline cyclosporine and steroid pulse therapy. The primary endpoint was a > 50% reduction in the urinary protein/creatinine ratio from baseline on day 169. Complete and partial remissions were also evaluated.

Results: Six patients with childhood-onset MRNS were enrolled. All patients were negative for pathogenic variants of podocyte-related genes. On day 169, five patients (83.3%) showed a > 50% reduction in the urinary protein/creatinine ratio, two patients showed partial remission, and two patients showed complete remission. No deaths occurred and severe adverse events occurred in two patients (infection in one patient and acute kidney injury in one patient). Three patients needed treatment for moderate-to-severe infection.

Conclusions: The study treatment effectively reduced the urinary protein/creatinine ratio in patients with childhood-onset MRNS. The adverse events in this study were within the expected range; however, attention should be paid to the occurrence of infections.

Keywords: Cyclosporine; MRNS; Methylprednisolone; Rituximab; SRNS.

Fig. 1

Study regimen. The investigators administered the first dose of steroid pulse therapy within 14 days after the date of registration (the first day of the first course of steroid pulse therapy was set as day 1). Rituximab was administered in four 375 mg/m² doses (maximum dose: 500 mg), separated by 1 week (days 8, 15, 22, and 29). The prednisolone tapering plan was as follows: (1) 30 mg/m²/day (maximum dose: 30 mg/day) divided into three portions for 4 weeks; (2) 30 mg/m²/dose (maximum dose: 30 mg/dose) once every other day until urine protein negativity was confirmed for three consecutive days; (3) 25 mg/m²/dose (maximum dose: 25 mg/dose) once every other day for 4 weeks; (4) 20 mg/m²/dose (maximum dose: 20 mg/dose) once every other day for 4 weeks; (5) 15 mg/m²/dose (maximum dose: 15 mg/dose) continued once every other day

Fig. 2

Changes in urinary protein-to-urinary creatinine ratio and serum albumin levels. The graphs (a–f) show the urinary protein-to-urinary creatinine ratio (solid line) and the serum albumin levels (dashed line) during the treatment and follow-up periods in each participant, cases 1–6, respectively. “S” means attainment of a > 50% reduction in the urinary protein-to-urinary creatinine ratio from baseline. The first dose of the first course of steroid pulse therapy was administered on day 1. Rituximab was administered in four 375 mg/m² doses at weekly intervals (8, 15, 22, and 29 days), followed by a maximum of four courses (dark green diamonds) of additional steroid pulse therapy (five courses in total, cyan squares). The reference line on the horizontal axis represents day 169, which was the end of the treatment period. Up/Uc, urinary protein-to-urinary creatinine ratio; Cr, creatinine; Alb, albumin

Fig. 3

Changes in estimated glomerular filtration rate (eGFR). The graph shows the eGFR values during the treatment and follow-up periods in each participant