What is the diagnosis for a patient with swollen legs, frothy urine, known hypertension (HTN), proteinuria, high blood pressure, hyperlipidemia, and pitting edema, with microscopy showing focal segmental glomerulosclerosis (FSGS) and electron microscopy showing diffuse foot process effacement?

Diagnosis: Primary Focal Segmental Glomerulosclerosis (Primary FSGS)

This patient has primary FSGS, characterized by the combination of full nephrotic syndrome (massive proteinuria, hypoalbuminemia, edema, hyperlipidemia), diffuse foot process effacement on electron microscopy, and FSGS lesions on light microscopy. 1, 2

Diagnostic Reasoning

Key Features Supporting Primary FSGS

• Diffuse foot process effacement (100% in this case) is the hallmark of primary FSGS, distinguishing it from secondary forms which typically show segmental (<50%) foot process effacement 1, 2, 3

• Complete nephrotic syndrome with proteinuria, frothy urine, hypoalbuminemia (implied by severe pitting edema to groin level), and hyperlipidemia indicates podocyte dysfunction from a circulating permeability factor 3

• The sudden onset and severity of presentation (edema extending to groin) suggests primary rather than secondary FSGS, which typically has more indolent presentation 1, 2

Excluding Secondary FSGS

The clinical presentation argues against secondary FSGS because: 1, 2

• Secondary FSGS typically presents with proteinuria <3.5 g/day or nephrotic-range proteinuria but preserved serum albumin >30 g/L 1
• Secondary forms show segmental foot process effacement, not the diffuse pattern seen here 1, 2
• Common causes of secondary FSGS (obesity with hilar variant, viral infections, drug toxicity, malignant hypertension) would not produce this degree of diffuse podocyte injury 1, 4, 5

Classification Framework

The KDIGO 2021 classification distinguishes: 1, 2

• Primary FSGS: Diffuse foot process effacement + nephrotic syndrome (often sudden onset, amenable to immunosuppressive therapy)
• Genetic FSGS: Familial, syndromic, or sporadic forms
• Secondary FSGS: Viral, drug-induced, or hyperfiltration-related with segmental foot process effacement
• FSGS of undetermined cause: Segmental foot process effacement without clear secondary cause

Critical Diagnostic Considerations

Evaluation for Secondary Causes

Before initiating immunosuppression, exclude: 1, 2

• Viral infections (HIV, hepatitis B/C, parvovirus B19)
• Drug exposure (heroin, pamidronate, interferon, anabolic steroids)
• Obesity-related glomerulopathy (BMI >30 kg/m², hilar variant on biopsy)
• Malignant hypertension (BP >180/120 mmHg with end-organ damage, thrombotic microangiopathy) 5

Genetic Testing Considerations

• Not routinely indicated unless there is family history of kidney disease, early age of onset (<25 years), or steroid resistance 1, 3
• Genetic forms (NPHS1, NPHS2, WT1, PLCE1 mutations) typically do not respond to immunosuppression 3

Clinical Significance

• Patients with nephrotic-range proteinuria >3.8 g/day have 35% risk of end-stage renal disease within 2 years if untreated 3
• Thromboembolism risk is 29% for renal vein thrombosis and 17-28% for pulmonary embolism due to loss of anticoagulant proteins 3
• Remission of proteinuria is the most significant predictor of renal survival in FSGS 3

Common Pitfalls to Avoid

• Do not assume secondary FSGS based solely on hypertension – the diffuse foot process effacement pattern is incompatible with secondary forms 1, 2
• Do not delay biopsy in adults with nephrotic syndrome – tissue diagnosis is essential to guide immunosuppressive therapy 1, 6
• Do not start immunosuppression without excluding secondary causes – this exposes patients to unnecessary toxicity without benefit 1