Into which glomerulopathy can minimal change disease potentially progress and why?

Minimal Change Disease Progression to Focal Segmental Glomerulosclerosis

Minimal change disease can progress to focal segmental glomerulosclerosis (FSGS), representing evolution along a continuum of the same underlying podocytopathy rather than transformation into a separate disease entity. 1

Mechanism of Progression

The evolution from MCD to FSGS occurs through progressive podocyte loss and injury:

• Substantial podocyte depletion uniformly results in segmental sclerosis in animal models, and FSGS represents a common pathway for virtually all progressive glomerulopathies 1
• Sequential biopsies and post-mortem studies in HIV-associated collapsing glomerulopathy have directly documented evolution from collapsing lesions to FSGS (NOS) 2
• The gradual development of FSGS in patients with non-remitting or relapsing idiopathic nephrotic syndrome has been well-documented 1

Why This Progression Occurs

Both MCD and FSGS share a common pathophysiology centered on podocyte dysfunction, which explains their relationship:

• Both diseases represent "podocytopathies" where the glomerular podocyte and cytoskeleton of its foot processes are the primary targets of injury 3
• MCD and idiopathic FSGS should be considered different manifestations of the same progressive disease rather than separate entities 1
• The key distinction is that FSGS represents an advanced stage of disease progression that develops when podocyte injury becomes severe enough to cause segmental scarring 1

Clinical Evidence Supporting This Continuum

Patients initially diagnosed with MCD can develop FSGS on repeat biopsy, particularly in steroid-resistant or frequently relapsing cases:

• A case report documented adult-onset MCD that failed steroids, calcineurin inhibitors, mycophenolate mofetil, and cyclophosphamide, with repeat biopsy showing collapsing FSGS 4
• The three leading histologic variants of idiopathic nephrotic syndrome—MCD, FSGS, and membranous nephropathy—are recognized as related entities 2

Distinguishing Features Despite Common Origin

Recent evidence suggests complement activation may distinguish established FSGS from MCD, even though they share pathogenic mechanisms:

• Urinary terminal complement activation fragments (sC5b9 and C5a) are markedly elevated in FSGS compared to MCD, despite similar proteinuria levels 5
• This complement activation may participate in the development of segmental lesions, with c-statistics of 0.96-1.00 for differentiating FSGS from MCD when proteinuria exceeds 3 g/g 5

Clinical Implications

Treatment responsiveness differs based on disease stage:

• Long-term kidney survival is excellent in MCD patients who respond to glucocorticoids, but less certain for those who do not respond 2
• FSGS should be considered an advanced stage of disease progression that is less likely to respond to treatment than earlier-stage MCD 1
• In clinical trials and practice, recognizing this continuum is essential for appropriate patient counseling and treatment selection 1