What are the causes of focal segmental glomerulosclerosis (FSGS)?

Causes of Focal Segmental Glomerulosclerosis

FSGS is not a single disease but a histological pattern of podocyte injury with four distinct etiologic categories: primary (immunologically mediated), genetic, secondary (viral/medication/adaptive), and FSGS of undetermined cause. 1

Classification Framework

The 2021 KDIGO guidelines fundamentally reconceptualized FSGS classification, moving away from the outdated "primary versus secondary" dichotomy to recognize the heterogeneous nature of this glomerular injury pattern. 1 This distinction is critical because treatment approaches, prognosis, and transplant recurrence risk differ dramatically between categories. 1

Primary FSGS

Primary FSGS is characterized by immunologic mechanisms with circulating permeability factors causing podocyte dysfunction. 1, 2

Clinical Features:

• Nephrotic-range proteinuria >3.5 g/day 1
• Serum albumin <3.0 g/dL 1
• Diffuse podocyte foot process effacement on electron microscopy 1
• Sudden onset of complete nephrotic syndrome 1
• Responds to immunosuppressive therapy 1

Genetic FSGS

Genetic mutations in podocyte structural or functional proteins account for 11-24% of adult steroid-resistant FSGS cases. 1

Gene Categories:

• Slit diaphragm proteins: NPHS1, NPHS2, CD2AP 1
• Cell membrane 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
• Type IV collagen genes: COL4A3, COL4A4, COL4A5 1

Clinical Implications:

Genetic testing is now recommended (a reversal from 2012 guidelines) for patients with familial disease, syndromic features, or steroid-resistant FSGS. 1 Identifying genetic causes prevents futile immunosuppression exposure and predicts low transplant recurrence risk. 1

Secondary FSGS

Secondary FSGS results from identifiable extrinsic causes producing direct podocyte injury or maladaptive responses to nephron stress. 3

Viral Causes:

• HIV infection (most established viral cause) 1, 3
• Parvovirus B19 1, 3

Medication-Induced:

• Interferon 1, 3
• Lithium 1, 3
• Bisphosphonates 1, 3
• Anabolic steroids 1, 3

Adaptive FSGS from Reduced Nephron Mass:

• Congenital: Oligomeganephronia, unilateral renal agenesis, kidney dysplasia 1, 3
• Acquired: Reflux nephropathy, cortical necrosis, surgical ablation, chronic allograft nephropathy 1, 3
• Functional loss: Sickle cell anemia, advanced CKD with reduced functioning nephrons 1, 3
• Prematurity (reduced nephron endowment at birth) 1, 3

Adaptive FSGS with Initially Normal Nephron Mass:

• Diabetes mellitus (hyperfiltration plus direct podocyte injury) 1, 3
• Hypertension (especially malignant hypertension) 1, 3
• Obesity (hyperfiltration injury) 1, 3
• Cyanotic congenital heart disease 1, 3

Distinguishing Features:

Secondary FSGS typically presents with non-nephrotic proteinuria (<3.5 g/day) or if nephrotic-range, albumin remains >3.0 g/dL. 3 These patients do not respond to immunosuppression and rarely experience post-transplant recurrence. 3

FSGS of Undetermined Cause (FSGS-UC)

FSGS-UC is a new 2021 category with features resembling maladaptive secondary FSGS but without identifiable cause. 1

This category should not receive immunosuppression; treatment focuses on RAS blockade, blood pressure control, and sodium restriction. 1

Critical Diagnostic Algorithm

Step 1: Assess Nephrotic Syndrome Severity

• Proteinuria >3.5 g/day AND albumin <3.0 g/dL with diffuse foot process effacement → likely primary FSGS 1
• Proteinuria <3.5 g/day OR albumin >3.0 g/dL → evaluate for secondary causes 1

Step 2: Screen for Secondary Causes

• HIV testing (mandatory) 3
• Medication review (interferon, lithium, bisphosphonates, anabolic steroids) 3
• Assess for reduced nephron mass (imaging for structural abnormalities, history of prematurity) 1, 3
• Evaluate systemic conditions (diabetes, obesity, hypertension) 3

Step 3: Consider Genetic Testing

• Mandatory indications: Family history of kidney disease, syndromic features, steroid-resistant disease 1
• Consider in: Early-onset disease (<25 years), consanguinity, lack of response to initial therapy 1

Step 4: Classify and Treat Accordingly

• Primary FSGS: High-dose glucocorticoids first-line 1
• Genetic/Secondary FSGS: No immunosuppression; treat underlying cause 1
• FSGS-UC: Conservative management only 1

Common Pitfalls

The most critical error is misdiagnosing secondary or genetic FSGS as primary FSGS, leading to inappropriate immunosuppression with significant toxicity and zero benefit. 3 Always complete the secondary cause workup before initiating immunosuppression. 1

Failing to identify treatable secondary causes (HIV requiring antiretroviral therapy, obesity requiring weight loss, offending medications requiring discontinuation) represents missed opportunities for targeted intervention. 3

Assuming all adult-onset FSGS is acquired disease overlooks the 11-24% with genetic causes, denying patients prognostic information and family counseling. 1