Outcome of Children Treated with Rituximab for Steroid-Resistant Nephrotic Syndrome: Renal Histopathology as a...

Steroid-resistant nephrotic syndrome (SRNS) in children remains a major therapeutic challenge. Although calcineurin inhibitors (CNIs) are commonly used as first-line therapy, a substantial proportion of patients fail to achieve remission, and prolonged use may result in nephrotoxicity. Rituximab has emerged as a potential therapeutic option for refractory SRNS; however, treatment responses appear variable, and the influence of underlying renal histopathology remains incompletely understood.

To evaluate the association between renal histopathological findings and clinical response to rituximab in children with calcineurin inhibitor-resistant steroid-resistant nephrotic syndrome (SRNS).

Study Design and Setting:This prospective observational study was conducted between 2011 and 2020 at a university-affiliated tertiary pediatric nephrology center. The study aimed to evaluate the efficacy of rituximab in children with calcineurin inhibitor-resistant steroid-resistant nephrotic syndrome (SRNS) and to examine the association between renal histopathological findings and treatment response. Twenty-four children aged 2-12 years were enrolled.Follow-up:Patients were followed prospectively after completion of rituximab therapy through regular clinical and laboratory assessments. The mean follow-up duration after the last rituximab infusion was 5.1 years (range: 6 months-8 years).Treatment Response Definitions:Complete remission was defined according to International Pediatric Nephrology Association (IPNA) recommendations as a urine protein-to-creatinine ratio (UPCR) ≤20 mg/mmol (≤0.2 mg/mg) or negative/trace proteinuria on dipstick testing on at least three consecutive occasions.Partial remission was defined as a UPCR >20 mg/mmol but <200 mg/mmol together with serum albumin ≥30 g/L.No response was defined as failure to achieve either complete or partial remission.Genetic Evaluation:Genetic testing was performed in all patients with focal segmental glomerulosclerosis (FSGS), classic minimal change disease (MCD), and MCD with IgM deposition. No pathogenic or likely pathogenic variants associated with monogenic steroid-resistant nephrotic syndrome were identified in the tested patients. Genetic testing was not performed in patients with IgA nephropathy, membranous nephropathy, C1q nephropathy, or dense deposit disease.

Twenty-four children with SRNS were included (13 males and 11 females; age range 2-12 years). Histopathological diagnoses included focal segmental glomerulosclerosis (FSGS) in 9 patients (37.5%), minimal change disease (MCD) in 4 (16.7%), MCD with IgM deposition in 6 (25.0%), dense deposit disease in 2 (8.3%), membranous nephropathy in 1 (4.2%), IgA nephropathy in 1 (4.2%), and C1q nephropathy in 1 (4.2%). Overall, 10 patients (41.7%) achieved complete remission and 3 (12.5%) achieved partial remission, predominantly among patients with MCD and MCD with IgM deposition. Responses were uncommon among patients with FSGS. Eleven patients (45.8%), all of whom were non-responders, progressed to end-stage kidney disease. No major adverse effects of rituximab were observed; mild infusion reactions occurred in three patients and mild cellulitis in one patient.

In this cohort of children with refractory SRNS, favorable responses to rituximab were observed predominantly among patients with CNI- resistant MCD and MCD with IgM deposition, whereas responses among patients with FSGS were uncommon. These findings suggest that renal histopathology may help identify patients more likely to benefit from rituximab therapy; however, the small sample size, heterogeneous histopathological distribution, and observational study design preclude definitive conclusions. Larger prospective multicenter studies incorporating comprehensive genetic evaluation are required to determine whether histopathology can serve as a reliable predictor of rituximab responsiveness.