What distinguishes the clinical picture of Focal Segmental Glomerulosclerosis (FSGS) from IgA Nephropathy (IgAN)?

Distinguishing Clinical Picture of FSGS vs IgAN

FSGS and IgA nephropathy present with fundamentally different clinical profiles: FSGS typically manifests with sudden-onset nephrotic syndrome (proteinuria >3.5 g/day, serum albumin <3.0 g/dL) and absent or minimal hematuria, while IgAN characteristically presents with episodic gross or persistent microscopic hematuria, often with sub-nephrotic proteinuria, and preserved serum albumin. 1, 2

Clinical Presentation Patterns

FSGS Clinical Features

• Proteinuria pattern: Sudden-onset nephrotic-range proteinuria (>3.5 g/day) with mean levels around 5.5 g/24hr at diagnosis 2
• Serum albumin: Typically <3.0 g/dL due to severe urinary protein losses 1, 3
• Hematuria: Absent or minimal; when present, only microscopic 2
• Edema: Prominent peripheral edema due to severe hypoalbuminemia 1
• Hyperlipidemia: Marked elevation secondary to nephrotic syndrome 1

IgAN Clinical Features

• Hematuria pattern: Present in 71-100% of cases; episodic gross hematuria (often following upper respiratory infections) or persistent microscopic hematuria is the hallmark 2, 4
• Proteinuria pattern: Variable, ranging from <1 g/day to nephrotic range; when nephrotic-range proteinuria occurs (in 82% of FSGS-like IgAN), serum albumin typically remains >3.0 g/dL 2, 4
• Edema: Less prominent than FSGS due to better-preserved serum albumin 2
• Hypertension: Common presenting feature 2

Demographic and Genetic Distinctions

FSGS Demographics

• Race: Over 35% of primary FSGS patients are Black, with strong association to APOL1 high-risk variants (G1, G2) in patients of African ancestry 1, 2
• Age: Can occur at any age but increasingly recognized in adults 1
• Gender: No strong gender predilection 2

IgAN Demographics

• Race: Predominantly affects White (67%), Hispanic (17%), and Asian (6%) populations; significantly less common in Black patients (11%) 2
• Age: Mean age around 35 years at diagnosis 2
• Gender: Male predominance (72%) 2

Pathophysiologic Mechanisms

FSGS Pathogenesis

• Primary FSGS: Circulating permeability factor(s) causing direct podocyte injury with diffuse foot process effacement on electron microscopy 1
• Secondary FSGS: Results from adaptive hyperfiltration (obesity, diabetes, reduced nephron mass), viral infections (HIV, parvovirus B19), or medications (interferon, lithium, bisphosphonates, anabolic steroids) 3, 1
• Genetic FSGS: Mutations in podocyte proteins (NPHS1, NPHS2, TRPC6, ACTN4, INF2) causing structural podocyte dysfunction 1

IgAN Pathogenesis

• Immune complex deposition: Mesangial IgA deposits (dominant immunoglobulin) with mesangial electron-dense deposits on electron microscopy 2
• Glomerular hypercellularity: Mesangial proliferation is characteristic, unlike FSGS which shows minimal mesangial changes 2, 5
• When FSGS-like lesions occur in IgAN: Represents secondary podocyte injury with segmental sclerosis, capillary collapse, and sometimes podocyte hypertrophy overlying sclerotic segments 2, 4

Histopathologic Distinctions (Kidney Biopsy Essential)

FSGS Histology

• Light microscopy: Segmental sclerosis affecting <50% of glomeruli initially, with podocyte loss and capillary collapse 1
• Immunofluorescence: Minimal or absent immune deposits; may show nonspecific IgM and C3 trapping in sclerotic segments 1
• Electron microscopy: Diffuse (>80%) podocyte foot process effacement extending beyond sclerotic segments 1
• Tubulointerstitial changes: Variable, more prominent in collapsing variant (classic HIVAN) with microcyst formation 1

IgAN Histology

• Light microscopy: Mesangial hypercellularity and matrix expansion; when FSGS-like lesions present, they show segmental sclerosis with adhesions and aberrant blood vessel formation connecting glomerular tuft to Bowman's capsule (characteristic feature in 15.7% of FSGS-like IgAN) 2, 5
• Immunofluorescence: Dominant or co-dominant mesangial IgA deposits (diagnostic hallmark); also C3, IgG, IgM may be present 2
• Electron microscopy: Mesangial electron-dense deposits; foot process effacement is segmental and less extensive than primary FSGS 2
• Podocyte features in FSGS-like IgAN: Podocyte hypertrophy (38% of cases) and tip lesions (7%) indicate podocyte injury and correlate with worse proteinuria and prognosis 4

Prognosis and Treatment Response

FSGS Outcomes

• Primary FSGS: High risk of progression to ESRD without treatment; responds to immunosuppression (corticosteroids, calcineurin inhibitors) in 30-40% of cases 1
• Secondary FSGS: Does not respond to immunosuppression; treatment targets underlying cause (antiretroviral therapy for HIV, weight loss for obesity, discontinue offending medications) 3, 1
• Recurrence post-transplant: Primary FSGS recurs in 30-50% of kidney transplants 3

IgAN Outcomes

• FSGS-like IgAN: Better renal survival than primary FSGS despite similar initial proteinuria and creatinine levels; only 9% progressed to ESRD at mean 70-month follow-up in one cohort 2
• Podocytopathic features: When podocyte hypertrophy or tip lesions present, patients have more rapid decline without treatment but show better response to immunosuppression 4
• Recurrence post-transplant: Rarely recurs compared to primary FSGS 3

Critical Diagnostic Algorithm

Step 1: Assess hematuria presence and pattern

• Absent/minimal hematuria → strongly favors FSGS 2
• Episodic gross or persistent microscopic hematuria → strongly favors IgAN 2

Step 2: Evaluate proteinuria severity and serum albumin

• Nephrotic proteinuria with albumin <3.0 g/dL → favors primary FSGS 1, 3
• Nephrotic proteinuria with albumin >3.0 g/dL → consider FSGS-like IgAN 2

Step 3: Consider demographic factors

• Black race with nephrotic syndrome → consider APOL1-associated FSGS 1
• White/Asian race with hematuria → favors IgAN 2

Step 4: Kidney biopsy is mandatory for definitive diagnosis

• Immunofluorescence showing dominant mesangial IgA = IgAN diagnosis regardless of FSGS-like histology 2
• Minimal immune deposits with diffuse foot process effacement = primary FSGS 1

Common Pitfalls to Avoid

Pitfall 1: Assuming all nephrotic syndrome is FSGS without checking for hematuria; missing IgAN diagnosis delays appropriate treatment 2

Pitfall 2: Treating secondary FSGS with immunosuppression causes significant toxicity without benefit; always exclude secondary causes (HIV, obesity, medications, reduced nephron mass) before initiating immunosuppression 3, 1

Pitfall 3: Relying solely on clinical features without kidney biopsy; approximately 7% of IgAN cases present with FSGS-like histology that requires immunofluorescence to distinguish from primary FSGS 2

Pitfall 4: In HIV-positive patients, failing to distinguish collapsing FSGS (classic HIVAN requiring antiretroviral therapy) from FSGS NOS or immune complex disease including IgAN; kidney biopsy with pathology-based description is essential to guide therapy 1