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

Causes of Focal Segmental Glomerulosclerosis (FSGS)

FSGS is not a single disease but a histologic pattern of glomerular injury caused by four distinct categories: primary (immunologic), genetic, secondary (from identifiable extrinsic causes), and undetermined causes. 1

Classification Framework

The 2021 KDIGO guidelines establish a modern classification system that divides FSGS into four subclasses based on etiology, which directly impacts treatment decisions and prognosis 1:

1. Primary FSGS (Immunologically Mediated)

• Caused by circulating permeability factors that directly injure podocytes 1, 2
• Presents with nephrotic-range proteinuria (>3.5 g/day), serum albumin <3.0 g/dL, and diffuse podocyte foot-process effacement on electron microscopy 1
• Responds to immunosuppressive therapy 1
• High risk of recurrence after kidney transplantation 2

2. Genetic FSGS

• Caused by mutations in podocyte structural or functional proteins (primarily type IV collagen or podocyte genes) 1
• Accounts for 11-24% of adult steroid-resistant FSGS cases 1
• Nearly 40 genes have been identified as causative 3
• Does not respond to immunosuppression 2
• Much less likely to recur after kidney transplantation 1

3. Secondary FSGS

Secondary FSGS results from identifiable causes producing direct podocyte injury or maladaptive responses to nephron stress 1, 4:

Viral-Associated FSGS:

• HIV infection (well-established cause) 4
• Parvovirus B19 (direct podocyte injury) 4

Medication-Associated FSGS (Direct Podocyte Toxicity):

• Interferon 4
• Lithium 4
• Bisphosphonates 4
• Anabolic steroids 4

Adaptive FSGS from Reduced Nephron Mass:

• Oligomeganephronia (congenital reduction in nephron number) 4
• Unilateral kidney agenesis 4
• Kidney dysplasia 4
• Cortical necrosis 4
• Reflux nephropathy 4
• Surgical kidney ablation 4
• Chronic allograft nephropathy 4
• Advanced chronic kidney disease with reduced functioning nephrons 4
• Sickle cell anemia (functional nephron loss) 4
• History of prematurity (reduced nephron endowment) 1, 4

Adaptive FSGS with Initially Normal Kidney Mass (Hyperfiltration Injury):

• Diabetes mellitus (hyperfiltration and direct podocyte injury) 4
• Hypertension, particularly malignant hypertension (endothelial and epithelial injury) 4
• Obesity (hyperfiltration injury) 4
• Cyanotic congenital heart disease 4

Nonspecific Scarring Pattern:

• Kidney scarring in other primary glomerular diseases can manifest as secondary FSGS histologically 4

4. FSGS of Undetermined Cause (FSGS-UC)

• Patients who do not clearly fit into primary, genetic, or secondary categories 1
• Should not receive immunosuppression 1

Key Clinical Distinctions for Diagnosis

Secondary FSGS typically presents with non-nephrotic range proteinuria (<3.5 g/day) OR nephrotic-range proteinuria with serum albumin >3.0 g/dL 1, 4, whereas primary FSGS presents with both nephrotic-range proteinuria AND low serum albumin (<3.0 g/dL) 1.

On electron microscopy, primary FSGS shows diffuse podocyte foot-process effacement, while secondary FSGS shows segmental foot-process effacement 5.

Diagnostic Workup Algorithm

For patients with nephrotic-range proteinuria and serum albumin <3.0 g/dL: Classify as likely primary FSGS and consider immunosuppression 1

For patients with non-nephrotic proteinuria OR albumin >3.0 g/dL: Workup for secondary causes 1:

• HIV testing 6
• Medication review (interferon, lithium, bisphosphonates, anabolic steroids) 4, 6
• Assessment for reduced nephron mass (history of prematurity, unilateral kidney, reflux nephropathy, prior kidney surgery) 4, 6
• Evaluation for obesity, diabetes, hypertension 4

Genetic testing is now recommended for: 1

• Patients with familial kidney disease or syndromic features
• Steroid-resistant FSGS
• Atypical presentations of primary or secondary FSGS 2

Critical Pitfalls to Avoid

Misdiagnosing secondary FSGS as primary FSGS leads to inappropriate immunosuppressive therapy with significant toxicity and no benefit 4, as secondary and genetic FSGS do not respond to immunosuppression 1, 2.

Failing to identify treatable secondary causes results in missed opportunities for targeted intervention: HIV requires antiretroviral therapy, obesity requires weight loss, and offending medications require discontinuation 4.

Patients may move from one category to another as more diagnostic information becomes available, requiring ongoing reassessment 1.