CLINICAL RESPONSE, EFFICACY AND CHANGES OF IMMUNE FUNCTION WITH RITUXIMAB TREATMENT IN CHILDHOOD DIFFICULT NEPHROTIC SYNDROME

Childhood idiopathic nephrotic syndrome (INS) is one of the most common kidney disease in children. Corticosteroid is the mainstay of treatment of this disease. But certain  percentage of this disease is difficult to treat. They are either responding with corticosteroids but required long term multiple immunosuppressive drugs e.g steroid dependent nephrotic syndrome(SDNS) or  poorly  responding and even do not response to corticosteroids e.g steroid resistant nephrotic syndrome(SRNS). Rituximab (RTX) is a newer drug. It is a monoclonal antibody  acts against CD20  of  B cell causing rapid depletion of B-cell and suppress the immunoglobulin production. Recent studies suggested a role of B-cell dysfunction in the pathogenesis of childhood idiopathic nephrotic syndrome. This led to a growing interest in rituximab as a potential treatment option for difficult to treat nephrotic syndrome patients. Different studies suggested that rituximab has high rate of remission   and maintenance of remission  in both the groups of patients. Aim of this study was to see the clinical response, efficacy and changes of immune function with rituximab treatment  in childhood  difficult nephrotic syndrome

After ethical approval (approval no BSMMU/2021/9918, Reg no 578), this prospective interventional study was conducted in the department of Pediatric Nephrology, Bangladesh Medical University (Former name Bangabandhu Sheikh Mujib Medical University), Bangladesh from January, 2022 to December, 2023 among 21 children of 1 to 18 years with SDNS and SRNS. SDNS patients with lack of steroid sparing effect (inability to sustain remission at a prednisone dose of 0.5 mg/kg every other day) or presence of significant steroid toxicity, despite treatment with oral cyclophosphamide (2 mg/kg per day for 12 weeks), levamisole (2.5 mg/kg for 6 months), mycophenolate mofetil (1200 mg/m2/day for 6 months), and calcineurin inhibitors (CNI) or  those showing CNI induced nephrotoxicity were included. SRNS patients with lack of remission despite therapy with calcineurin inhibitors for 6 month, presence of significant nephrotoxicity on renal biopsy were included. Study was initiated after taking informed written consent from parents. RTX was administered at a dose of 375 mg/m2/dose and repeated bi-weekly 1-4 times depending upon clinical response. RTX was given in SDNS patients during corticosteroid-induced urinary remission. Clinical response was labeled as complete remission, partial remission and no remission. Complete blood count(CBC), serum albumin, serum electrolyte and creatinine, serum calcium, fasting glucose, lipid profile level, HBV surface antigen, Anti HCV level, urine R/M/E, culture sensitivity test, Urine protein creatinine ratio, CXR, serum IgG, IgA, IgM level, serum  CD19 count were performed before administering RTX.  Premedication with oral acetaminophen (15 mg/kg), diphenhydramine (0.5 mg/ kg), intravenous hydrocortisone (4 mg/kg) was given 30 minutes before infusion of the RTX. RTX was diluted at a concentration of 1 mg/ml of 5% glucose solution. Infusion was started at 5 ml/hour and increased by 5 ml every ½ hour as tolerated by blood pressure (BP) and heart rate (HR). Maximum infusion rate was 50 ml/hour unless patient had a previous reaction, then maximum infusion rate was capped at 25 ml/hour. Monitoring of heart rate(HR), respiratory rate (RR), blood pressure(BP), temperature, oxygen saturation (SpO2) was done every 15 minutes for 1st hour, thereafter hourly. If BP falls to <100/50 mmHg , HR >120/minute, SpO2 <95% on room air, infusion was stopped and rechecked. When parameters stabilize, infusion was restarted at previous tolerated rate and infusion was completed over 3 to 4 hours.  Patients were followed up at 15 days, thereafter at 1, 3, 6, and 12 months after the first  dose of rituximab treatment. Complete blood count, Serum albumin, spot urine protein/creatinine ratio (Up/Uc) in the first morning sample were done during follow up and also during relapse. Serum CD19 counts and immunoglobulin G (IgG), immunoglobulin M (IgM), immunoglobulin A (IgA) level were done during follow up. Data was analyzed by SPSS software version 27. Continuous data was expressed as mean and SD, categorical data was expressed as frequency and percentage. The difference between two groups was analyzed using t-test and p <0.05 was considered as significant.

The mean age of study subjects was 9.5 year. SDNS and SRNS were 52% and 48% respectively. Sixty percent of SRNS cases were initial steroid resistant. Most of the study subjects had minimal change disease(MCD, 42.9%), 71% patients got 2 or more than 2 immunosuppressive drugs, 38.1% patient got one dose of RTX, 52.4% patients developed remission after 1st dose of RTX. Among the cases, complete remission, partial remission and no remission were 52.4%, 19%  and 28.6% respectively. All the SDNS cases and 40% of SRNS cases underwent remission (p=0.004). Among the RTX  responded cases, only 36.4% SDNS cases developed relapse whereas 75% SRNS cases developed relapse within 6months of RTX therapy (p=0.28). Only 27.3% SDNS cases whereas 75% SRNS cases developed relapse between 6-12 months of RTX therapy (p=0.003). Following the RTX therapy, 23.8% cases had no complication but 33.3% had mild upper respiratory tract infection (URTI) (table 1). The rate of B (CD19) cell depletion (< 5/ul) was 33% at 15 days after the 1st dose dose of RTX treatment, only 5.5% depletion  at 6months and the rate of B cell recovery was 100% at 9–12 months after the first dose of RTX treatment. There was no changes in serum level of IgG but IgM level was reduced from  1 month and it was not recovered upto12 months of RTX therapy. Serum IgA level also reduced from 1 month but it had variable rate of recovery from 6months to 12months.

Table 1:  Baseline characteristics, efficacy and complications of  rituximab therapy in childhood difficult nephrotic syndrome (N=21)

Fisher exact test, MCD; Minimal change disease, FSGS; Focal segmental glomerulosclerosis, MPGN; Membranoproliferative glomerulonephritis, MesPGN; Mesangioproliferative glomerulonephritis

Table 2: Changes of immune function with rituximab therapy in childhood difficult nephrotic syndrome (N=21)

Rituximab induced complete remission was 52.4% in childhood difficult nephrotic syndrome cases. All SDNS patient developed remission but only 40% SRNS patients developed remission. Relapse rate also higher in SRNS cases. One third of the cases developed mild URTI and 23.8% didn’t have any complication. Only one third of the cases developed B-cell depletion initially but typically recovered at 9-12 months of 1st dose of rituximab therapy. Serum IgG level was maintained but IgM level was reduced upto 12months.