Which of the following statements about focal segmental glomerulosclerosis is correct?

The Correct Answer is C: HIV infection is a cause of secondary FSGS

Statement C is correct: HIV infection is a well-established cause of secondary focal segmental glomerulosclerosis. 1, 2

Analysis of Each Statement

A) Non-invasive diagnostic tests - INCORRECT

There are no non-invasive diagnostic tests to confirm FSGS. Kidney biopsy is essential for diagnosis, as FSGS is a histological pattern that can only be definitively identified through tissue examination 3. The biopsy is necessary to distinguish FSGS from other glomerular diseases and to differentiate between primary, secondary, and genetic forms 2.

B) Kidney biopsy is not necessary - INCORRECT

Kidney biopsy is absolutely necessary for FSGS diagnosis. Unlike minimal change disease in children where clinical presentation may suffice, FSGS requires histological confirmation in both adults and children 3, 2. The biopsy provides critical information about:

• The specific FSGS variant (collapsing, tip lesion, hilar, etc.)
• Degree of foot process effacement
• Presence of immune deposits
• Distinction between primary and secondary causes

C) HIV infection causes secondary FSGS - CORRECT

HIV infection is definitively recognized as a cause of secondary FSGS, specifically HIV-associated nephropathy (HIVAN) 1, 2. The evidence shows:

• Classic HIVAN presents as collapsing glomerulopathy with characteristic features
• Direct HIV infection of renal epithelial cells causes podocyte injury
• Parvovirus B19 is also listed as a viral cause of secondary FSGS 1
• Other secondary causes include medications (interferon, lithium, bisphosphonates), obesity, and reduced kidney mass 1

D) Not associated with hereditary abnormalities - INCORRECT

FSGS is strongly associated with hereditary abnormalities. The 2021 KDIGO guidelines specifically recognize genetic FSGS as a distinct category 4, 5. Over 60 genes have been identified that cause FSGS, including:

• Slit diaphragm proteins (NPHS1, NPHS2, CD2AP)
• Cell membrane proteins (TRPC6, LAMB2)
• Cytoskeletal proteins (ACTN4, INF2, MYO1E)
• APOL1 risk alleles (particularly prevalent in African Americans) 1, 6

Genetic testing is now recommended for selected patients, particularly those with familial disease, syndromic features, or steroid-resistant disease 7, 8.

E) No treatment available - INCORRECT

Multiple treatment options exist for FSGS, though they vary by etiology 4, 7:

For Primary FSGS:

• High-dose oral glucocorticoids are first-line therapy (Grade 1C recommendation) 4, 7
• Prednisone 1 mg/kg/day (maximum 80 mg) for 4-16 weeks until remission
• Alternative agents include calcineurin inhibitors, cyclophosphamide, rituximab, and mycophenolate 9, 4

For Secondary FSGS:

• Treat underlying cause (antiretroviral therapy for HIV, weight loss for obesity)
• RAS blockade and blood pressure control
• Immunosuppression is NOT indicated 7

For Genetic FSGS:

• Supportive care with RAS blockade
• Immunosuppression is generally ineffective 1
• Novel therapies like inaxaplin for APOL1-associated disease are in development 10

Key Clinical Pitfalls

1. Do not start immunosuppression without excluding secondary and genetic causes - this exposes patients to unnecessary toxicity without benefit 7

2. Distinguish between nephrotic syndrome (albumin <30 g/L, proteinuria >3.5 g/day) and nephrotic-range proteinuria alone - only the former warrants consideration of immunosuppression in primary FSGS 4

3. Consider genetic testing in adults with steroid-resistant FSGS, family history, or early-onset disease - up to 11-24% of adults with steroid-resistant FSGS have genetic causes 7, 8