What are the causes of secondary Focal Segmental Glomerulosclerosis (FSGS)?

Causes of Secondary FSGS

Secondary FSGS results from podocyte injury mediated by viral infections, medications, adaptive responses to reduced or stressed nephron mass, and systemic conditions that cause glomerular hyperfiltration or hemodynamic stress. 1

Viral-Associated Secondary FSGS

• HIV infection is a well-established viral cause of secondary FSGS 1
• Parvovirus B19 can also trigger secondary FSGS through direct podocyte injury 1

Medication-Associated Secondary FSGS

The following medications can cause direct podocyte toxicity leading to secondary FSGS:

• Interferon 1
• Lithium 1
• Bisphosphonates 1
• Anabolic steroids 1

Adaptive Secondary FSGS Due to Reduced Nephron Mass

This category represents maladaptive responses to loss of functioning nephrons, causing hyperfiltration injury in remaining glomeruli: 1, 2

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

Adaptive Secondary FSGS with Initially Normal Kidney Mass

These conditions cause glomerular hyperfiltration and hemodynamic stress despite normal baseline nephron number: 1, 2

• Diabetes mellitus (causes hyperfiltration and direct podocyte injury) 1, 3
• Hypertension (particularly malignant hypertension causing endothelial and epithelial injury) 1, 4
• Obesity (causes hyperfiltration injury) 1, 2
• Increased muscle mass in non-obese individuals (causes hyperfiltration from elevated metabolic demand) 5
• Cyanotic congenital heart disease 1

Secondary FSGS as Nonspecific Scarring Pattern

• Kidney scarring in other primary glomerular diseases can manifest as secondary FSGS histologically, and treatment should target the underlying primary disease rather than the FSGS pattern itself 1

Key Clinical Distinctions

Distinguishing secondary from primary FSGS has critical therapeutic implications because immunosuppressive therapy is not indicated in secondary FSGS and may cause harm: 1, 6

• 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
• Electron microscopy shows segmental (not diffuse) foot process effacement in secondary FSGS, unlike the widespread effacement seen in primary FSGS 6
• Secondary FSGS does not respond to immunosuppression and rarely recurs after kidney transplantation 2, 6

Common Pitfalls

• Misdiagnosing secondary FSGS as primary FSGS leads to inappropriate immunosuppressive therapy with significant toxicity and no benefit 3, 6
• Failing to identify treatable secondary causes (HIV requiring antiretroviral therapy, obesity requiring weight loss, offending medications requiring discontinuation) results in missed opportunities for targeted intervention 1