Focal segmental glomerulosclerosis (FSGS) due to mutation in the NPHS2 gene encoding podocin is classified as which variant of FSGS in the Columbia classification, and why does it fail to respond to steroid therapy?

• A Collapsing variant; podocin loss causes parietal epithelial cell activation but is intrinsically steroid-unresponsive
• B Tip lesion variant; podocin deficiency disrupts tubular anchoring of the slit diaphragm
• C Perihilar variant; podocin mutations cause hyperfiltration-mediated injury in juxtamedullary nephrons
• D Not otherwise specified (NOS) variant; genetic (primary podocytopathy) causes structural slit diaphragm deficiency unresponsive to immune suppression ✓

Explanation

Genetic FSGS due to NPHS2 (podocin) mutations is typically classified as the NOS or tip variant on histology, but the critical point is that it is a primary structural podocytopathy — not immune-mediated. Podocin is an integral membrane protein at the slit diaphragm that interacts with nephrin, CD2AP, and TRPC6 channels; its absence causes constitutive slit diaphragm dysfunction and protein leak. Since there is no immune effector mechanism, glucocorticoids (which reduce circulating permeability factors or modulate immune cells) are ineffective, and these patients are steroid-resistant from the outset.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.