Steroid-Resistant Idiopathic Nephrotic Syndrome Reveals a Distinct Maladaptive Molecular State

Area of Science:

• Nephrology
• Proteomics
• Molecular Biology

Background:

• Idiopathic nephrotic syndrome (iNS) is clinically classified by treatment response.
• The molecular basis of multidrug resistance in iNS is poorly understood.
• This study investigates whether multidrug-resistant disease represents a distinct biological state.

Purpose of the Study:

• To identify molecular differences between steroid-dependent (SDNS), multidrug-dependent (MDNS), and multidrug-resistant nephrotic syndrome (MRNS).
• To characterize the proteomic and functional profiles associated with MRNS.
• To explore the potential for biologically informed disease stratification in iNS.

Main Methods:

• Serum proteomic profiling using LC-MS/MS in 165 patients with iNS and healthy donors.
• Stratification of patients into SDNS, MDNS, and MRNS groups.
• Differential protein expression analysis, pathway enrichment, multivariate modeling, ELISA validation, and functional assays in podocytes and PBMCs.

Main Results:

• A 35-protein signature differentiated MRNS from MDNS and SDNS.
• Dystroglycan 1 (DAG1), CD44, and TARBP2 were key proteins distinguishing phenotypes.
• MRNS sera induced cytoskeletal, proteostasis, and autophagy alterations in podocytes, with inverse BIP/pAKT distribution.

Conclusions:

• MRNS exhibits a distinct proteomic and functional profile.
• This profile is characterized by coordinated stress-response dysregulation.
• Findings support biologically informed stratification of iNS, identifying MRNS as a unique disease state.