INTRODUCTION: Idiopathic nephrotic syndrome (iNS) shows marked variability in treatment response, yet the molecular basis of multidrug resistance remains unclear. We hypothesized that multidrug-resistant nephrotic syndrome (MRNS) represents a distinct biological state rather than simply severe disease activity. METHODS: Serum proteomic profiling (LC–MS/MS) was performed in 165 pediatric and young adult patients with iNS, stratified by therapeutic phenotype (MRNS, steroid-dependent [SDNS], and multidrug-dependent [MDNS]). Differential protein expression was analyzed using pathway enrichment and machine learning–based approaches. Key biomarkers were validated by ELISA. Functional effects were evaluated in human podocytes exposed to patient-derived sera and in their peripheral blood mononuclear cells (PBMCs). RESULTS: Of 810 identified proteins, 322 differed significantly among groups. A 35-protein Random Forest signature discriminated MRNS from SDNS and MDNS. Integration of machine learning approaches identified dystroglycan 1 (DAG1), CD44 antigen (CD44), and RISC-loading complex subunit (TARBP2) as major contributors to group separation. Functional analyses revealed cytoskeletal disorganization, altered autophagy, inflammasome dysregulation, and increased endoplasmic reticulum stress in podocytes exposed to MRNS sera. A central mechanistic axis was the stress–survival imbalance with inverse regulation of the endoplasmic reticulum chaperon BIP (GRP78) and phosphorylated AKT (Ser473), a pattern also observed in peripheral blood mononuclear cells from MRNS patients. In contrast, sera from patients in remission showed phenotypes similar to those of healthy donors. CONCLUSIONS: MRNS represents a distinct molecular state characterized by systemic and organ-persistent stress activation and disrupted cellular homeostasis, whereas remission is characterized by a near-healthy profile. These findings support biomarker-guided stratification and therapeutic strategies aimed at restoring cellular balance rather than broadly suppressing immunity.