Nephropathology Essentials – Focal and Segmental Glomerulosclerosis (FSGS): A Clinicopathological Correlation and Case-Based Approach Toward the Correct Diagnosis

In this session of Nephropathology Essentials, Dr. Rennke presented a case-based approach to FSGS. Our Moderator’s Notes are derived from his live presentation, which you can watch here:

Moderator’s Notes

Author: Dr. Pravir V. Baxi
Editors: Dr. Ali Poyan Mehr

Key points:

  • Podocyte (visceral epithelial cell) injury is the hallmark of proteinuria
    • Diffuse podocytopathy typically manifests as nephrotic syndrome with edema, hypoalbuminemia, and nephrotic range proteinuria
    • Focal podocytopathy typically results in modest amount of proteinuria without overt nephrotic syndrome features
    • Important to further differentiate from acquired and genetic causes
  • Dr. Rennke shared his approach to the differential diagnosis of FSGS pattern of injury:
    • Idiopathic or Primary FSGS
      • Etiology –“Permeability Factor”
      • Sudden onset nephrotic syndrome
      • Pathological Characteristics
        • Normal sized glomeruli, diffuse effacement of foot process , no significant chronicity
    • Familial and Genetic FSGS
      • Genetic Podocytopathies with focal Injury
        • Include ACTN4 (alpa-actinin-4), TRPC6 (canonical transient receptor potential 6), INF2 (formin family of actin-regulating proteins), APOL1 mutations
      • Genetic Podocytopathies with Diffuse Injury
        • Include NPHS2 (podocin), NPHS1 (nephrin), PLC31 (phospholipase C epsilon), WT1 (wilms tumor gene) mutations
    • Secondary or Adaptive FSGS
      • Initial loss of functioning nephrons followed by adaptations
        • Examples: Unilateral renal agenesis, segmental hypoplasia and oligomeganephronie, reflux nephropathy, primary glomerulopathies, partial cortical necrosis, sickle cell disease, atheroembolic disease, cystic disease
      • Without an initial loss of nephrons but with functional maladaptation
        • Diabetic Nephropathy, Obesity-associated, Glycogen storage disease
      • Slowly progressive proteinuria without edema, typically hx of prior kidney disease
      • Pathological Features
        • Glomerular hypertrophy
        • Focal foot process effacement (primarily preserved)
    • Segmental Glomerular Scarring

Selected References:

Rosenberg AZ, Kopp JB. Focal Segmental Glomerulosclerosis. Clin J Am Soc Nephrol. 2017

D’Agati VD, Kaskel FJ, Falk RJ. Focal segmental glomerulosclerosis. N Engl J Med. 2011

Fogo AB. Causes and pathogenesis of focal segmental glomerulosclerosis. Nat Rev Nephrol. 2015