Efficacy and Safety of Therapies for Pediatric Steroid-Resistant Idiopathic Nephrotic Syndrome: A Systematic Review of the Last Decade

Steroid-resistant nephrotic syndrome (SRNS) represents a major therapeutic challenge in pediatric nephrology, being associated with poor prognosis and increased risk of progression to chronic kidney disease. Over the past decade, several therapeutic strategies have been evaluated, but evidence regarding their efficacy and safety remains heterogeneous. The main objective of this study is to systematically review the efficacy and safety of therapies for pediatric idiopathic SRNS. We systematically searched PubMed/MEDLINE, SCOPUS, Web of Science, ScienceDirect, BMC Pediatrics, and Cochrane Library/CENTRAL for studies published between January 2014 and February 2024. Randomized controlled trials (RCTs), nonrandomized experimental studies, and prospective cohorts evaluating therapeutic interventions in children with idiopathic SRNS were included. Study selection, data extraction, and quality assessment were performed independently by two reviewers, using Joanna Briggs Institute (JBI) tools. The review protocol was registered in PROSPERO (CRD42024558619). Out of 12,678 records identified, 10 studies fulfilled the eligibility criteria, comprising 441 pediatric patients. Five were RCTs, four non-randomized experimental studies, and one prospective cohort. Interventions evaluated included tacrolimus (TAC), cyclosporine A (CsA), mycophenolate mofetil (MMF), cyclophosphamide (oral and intravenous), leflunomide (LEF), rituximab (RTX), and ofatumumab (OFA), mostly in combination with steroids. TAC demonstrated higher remission rates compared with CsA and MMF, with fewer adverse effects. Triple immunosuppressive therapy (TAC + steroids + antimetabolite) improved both short- and long-term remission rates compared with two-drug (dual) regimens. RTX showed partial efficacy, reducing proteinuria and steroid burden, while OFA did not achieve significant benefit over placebo. MMF following RTX was associated with higher relapse-free survival compared with CsA. Oral and intravenous cyclophosphamide had similar efficacy and safety profiles. Across studies, adverse effects were predominantly steroid- or calcineurin inhibitor (CNI)-related, while severe events included infections, hematological toxicity, and rare drug-related nephrotoxicity. Current evidence suggests TAC-based regimens offer superior efficacy and safety compared with CsA or MMF in pediatric idiopathic SRNS. Anti-CD20 monoclonal antibodies present variable results, with RTX showing limited but measurable benefit and OFA lacking efficacy. MMF appears favorable after RTX compared to CsA, while cyclophosphamide shows no advantage between oral and intravenous administration. Despite progress, evidence remains limited by small sample sizes and heterogeneity, underscoring the need for large-scale, multicenter trials to optimize therapeutic strategies.