FSGS Causes
FSGS is a histological pattern of podocyte injury with four distinct etiologic categories: primary (immunologically mediated), genetic (monogenic mutations in ~40 genes), secondary (viral, medication, or adaptive changes from reduced nephron mass), and undetermined cause. 1, 2
Primary FSGS
- Idiopathic/immunologically mediated - caused by circulating permeability factors that damage podocytes
- Typically presents with nephrotic-range proteinuria (>3.5 g/day) and serum albumin <3.0 g/dL
- Responds to immunosuppressive therapy 1, 2
Genetic FSGS
Mutations in approximately 40 genes affecting podocyte structure and function:
Slit Diaphragm Proteins
- NPHS1, NPHS2, CD2AP 1
Cell Membrane-Associated Proteins
- TRPC6, PTPRO, LAMB2, ITGB4, CD151, ITGA3 1
Cytosolic/Cytoskeletal Proteins
- ACTN4, PLCE1, MYH9, INF2, MYO1E, ARHGAP24 1
Nuclear Proteins
- WT1, SMARCAL1 1
Mitochondrial Components
- mtDNA-A3242G, COQ2, COQ6 1
High-Risk Alleles
- APOL1 risk variants in individuals of sub-Saharan African ancestry - significantly increases FSGS risk 2
Genetic testing is now recommended for steroid-resistant FSGS, familial kidney disease, or syndromic features - 11-24% of adults with steroid-resistant FSGS have identifiable genetic mutations 2
Secondary FSGS
Virus-Associated
- HIV
- Parvovirus B19 1
Medication-Associated
- Interferon
- Lithium
- Bisphosphonates
- Anabolic steroids 1
Adaptive Changes from Reduced Nephron Mass
- Oligomeganephronia
- Unilateral kidney agenesis
- Kidney dysplasia
- Cortical necrosis
- Reflux nephropathy
- Surgical kidney ablation
- Chronic allograft nephropathy
- Advanced CKD with reduced functioning nephrons
- Sickle cell anemia
- Prematurity 1, 2
Adaptive Changes with Initially Normal Kidney Mass
- Diabetes mellitus
- Hypertension
- Obesity
- Cyanotic congenital heart disease 1
Nonspecific Pattern
- Kidney scarring in other primary glomerular diseases 1
Critical Clinical Distinction
Distinguishing primary from secondary/genetic FSGS is therapeutically essential - immunosuppression is indicated only for primary FSGS, while secondary forms require treatment of the underlying cause (antiretroviral therapy for HIV, weight loss for obesity, discontinuing offending medications) and genetic forms do not respond to immunosuppression 1, 2
Common pitfall: Segmental scarring frequently occurs in other primary glomerular diseases - treatment should target the primary disease, not the FSGS pattern itself 1
Pathophysiology
All FSGS forms converge on podocyte injury and loss through multiple mechanisms:
- Genetic mutation-induced abnormality in podocyte function
- Inability to adapt to hypertrophy-inducing or hemodynamic stress
- Abnormalities in cell energetics
- Inflammatory damage 1
FSGS is a histological phenotype, not a single disease - this explains the clinical variability in presentation, natural history, and response to therapy 1