What are the diagnostic criteria and initial treatment options for a patient presenting with nephrotic syndrome, characterized by heavy proteinuria, low serum albumin levels, hyperlipidemia, and edema?

Nephrotic Syndrome Diagnosis

Nephrotic syndrome is diagnosed when proteinuria ≥3.5 g/24 hours (or urine protein-to-creatinine ratio >300-350 mg/mmol) occurs with serum albumin <3.0 g/dL in adults (<2.5 g/dL in children), typically accompanied by edema. 1, 2

Diagnostic Criteria

Core Clinical Features

• Proteinuria threshold: ≥3.5 g/24 hours in adults or ≥40 mg/h/m² in children 2
• Hypoalbuminemia: Serum albumin <3.0 g/dL in adults or ≤2.5 g/dL in children 1, 2
• Edema: Typically periorbital in the morning, progressing to dependent pitting edema throughout the day due to decreased oncotic pressure 1
• Hyperlipidemia: Elevated total cholesterol, LDL-C, and triglycerides as a compensatory mechanism for plasma protein loss 1

Critical caveat: Nephrotic syndrome can occur without nephrotic-range proteinuria when concurrent liver disease reduces albumin synthesis—look for severe hypoalbuminemia with proteinuria <3.5 g/day if hepatic dysfunction is present 3

Laboratory Assessment

Initial workup must include: 2

• Quantify proteinuria using 24-hour urine collection or spot urine albumin-to-creatinine ratio (uACR ≥300 mg/g indicates severely increased albuminuria) 2
• Serum albumin measurement (note assay type: bromocresol green vs. bromocresol purple, as BCG 2.5 g/dL ≈ BCP 2.0 g/dL) 2
• Complete blood count with platelets 2
• Serum electrolytes, kidney function tests (creatinine, eGFR) 2
• Lipid profile (total cholesterol, LDL-C, HDL-C, triglycerides) 2
• Urinalysis with microscopy to look for fatty casts/oval fat bodies (nephrotic) vs. RBC casts (nephritic) 1

Secondary cause evaluation: 2

• Complement levels (C3, C4) to assess for immune-mediated disease 2
• Antinuclear antibody (ANA) and anti-dsDNA if systemic lupus erythematosus suspected 2
• Hepatitis B and C serologies, HIV testing (particularly in high-risk populations) 2
• Serum and urine immunoelectrophoresis/immunofixation plus serum free light chains for all adults to exclude paraprotein-related disease 2
• Medication review to identify nephrotoxic agents 2

Imaging

• Renal ultrasound to assess kidney size and echogenicity, particularly before potential biopsy 2
• Abdominal ultrasound to evaluate for ascites 2
• Cardiac ultrasound to check for effusions and left ventricular mass 2

Kidney Biopsy Indications

Adults: Kidney biopsy should be performed within the first month after nephrotic syndrome onset, preferably before starting immunosuppressive treatment, to establish specific histologic diagnosis 2

Exception: Biopsy may be deferred in adults with positive serum anti-phospholipase A2 receptor antibodies (diagnostic of membranous nephropathy) 1, 2

Children: Kidney biopsy is NOT routinely performed at initial presentation in children <12 years; empiric glucocorticoid therapy is standard 1, 2

Biopsy indicated in children for: 1

• Steroid resistance
• Age ≥12 years
• Atypical features suggesting nephritic syndrome

Technical Requirements for Biopsy

The biopsy sample must include: 2

• At least 8 glomeruli for light microscopy with H&E, PAS, Masson's trichrome, and silver stain
• Immunofluorescence for IgG, C3, IgA, IgM, C1q, κ and λ light chains
• Electron microscopy to facilitate recognition of proliferative and membranous lesions

**In advanced CKD (GFR <30 mL/min/1.73 m²):** Biopsy may still be considered if there is evidence of active disease and kidney size >9 cm in length 2

Initial Treatment

Supportive Care (All Patients)

Fluid and sodium management: 2

• Sodium restriction
• Loop diuretics for edema control (furosemide is commonly used) 4
• Reduce diuretic doses in patients at risk for hypovolemia before initiating SGLT2 inhibitors 5

Antiproteinuric therapy: 2

• RAS inhibition with ACE inhibitors or ARBs to reduce proteinuria and blood pressure 2
• Target blood pressure ≤125/80 mmHg 4

Lipid management: 2

• Statin therapy for persistent hyperlipidemia, particularly with other cardiovascular risk factors 2

Thromboembolism Risk Assessment and Prophylaxis

High-risk criteria requiring consideration of prophylactic anticoagulation: 2

• Serum albumin <2.0-2.5 g/dL (particularly <2.9 g/dL) 1, 2
• Additional risk factors: proteinuria >10 g/day, BMI >35 kg/m², heart failure, recent surgery, prolonged immobilization 2
• Membranous nephropathy carries higher VTE risk than other causes 2

Anticoagulation approach: 2

• Warfarin is the anticoagulant of choice with target INR 2-3, requiring frequent monitoring due to fluctuating albumin-protein binding 2
• Factor Xa inhibitors and direct thrombin inhibitors are NOT recommended due to unpredictable pharmacokinetics from significant albumin binding and urinary losses 2

Disease-Specific Immunosuppression

Treatment depends on underlying histologic diagnosis and classification:

For Primary FSGS with Nephrotic Syndrome

First-line therapy: 4

• Prednisone 1 mg/kg/day (maximum 80 mg) or alternate-day dose of 2 mg/kg (maximum 120 mg) 4
• Continue high-dose corticosteroids for minimum of 4 weeks up to maximum of 16 weeks as tolerated, or until complete remission achieved, whichever is earlier 4
• If complete remission achieved: taper slowly over 6 months after achieving complete remission 4

Alternative first-line therapy (for patients with contraindications to corticosteroids): 4

• Calcineurin inhibitors (CNIs) for patients with uncontrolled diabetes, psychiatric conditions, severe osteoporosis, or obesity with elevated HbA1c 4
• Cyclosporine: 3-5 mg/kg/day in 2 divided doses (target trough 100-175 ng/ml) 4
• Tacrolimus: 0.05-0.1 mg/kg/day in 2 divided doses (target trough 5-10 ng/ml) 4
• Cyclosporine may be preferred over tacrolimus due to lesser tendency to precipitate diabetes 4

For Minimal Change Disease

• Cyclosporin as alternative to high-dose corticosteroids: Starting dose 2 mg/kg/day, gradually increase to maximum 4-6 mg/kg/day based on pharmacokinetic monitoring 2
• Continue for minimum of 6 months, with slow tapering by 0.5 mg/kg/month after complete remission, maintaining for 1-2 years 2

For Lupus Nephritis with Nephrotic Syndrome

• Initial therapy with corticosteroids combined with either cyclophosphamide or mycophenolate mofetil 4
• Consider anticoagulant treatment when serum albumin <20 g/L 2

FSGS-Specific Evaluation

Classification into one of four categories guides treatment: 4, 5

1. Primary FSGS: Diffuse foot process effacement, nephrotic syndrome with sudden onset—amenable to immunosuppression 4
2. Genetic FSGS: Familial, syndromic, or sporadic—genetic testing indicated; do NOT use immunosuppression 4, 5
3. Secondary FSGS: Viral, drug-induced, glomerular hyperfiltration (obesity, prematurity)—do NOT use immunosuppression 4, 5
4. FSGS of undetermined cause: Segmental foot process effacement, proteinuria without full nephrotic syndrome—supportive therapy, monitor closely 4

Genetic testing should be considered for: 5, 2

• Familial kidney disease
• Syndromic features
• Steroid-resistant FSGS
• Early-onset cases
• History of prematurity (reduced nephron number) 5

In adults with steroid-resistant nephrotic syndrome and FSGS on biopsy, 11-24% will have disease-causing variants primarily in type IV collagen or podocyte genes 5

Critical Pitfalls to Avoid

• Do not dismiss nephrotic syndrome based solely on normal serum albumin—early or partial nephrotic syndrome may present atypically, particularly with albumin assay variability 1
• Do not delay kidney biopsy in adults—biopsy should be performed within first month, preferably before immunosuppression 2
• Do not overlook thromboembolism risk—assess beyond albumin level alone; consider BMI, heart failure, recent surgery, immobilization 2
• Do not use immunosuppression in secondary or genetic FSGS—failing to distinguish primary from secondary causes has critical treatment implications 5
• Do not routinely infuse albumin—KDIGO guidelines do not recommend albumin infusion as standard management 2

Monitoring

Follow-up schedule: 2

• Every 2-4 weeks for first 2-4 months
• Then every 3-6 months for renal and extra-renal disease activity
• Regular assessment of proteinuria, serum albumin, kidney function
• Monitor for complications: thromboembolism, infections, acute kidney injury

Remission of proteinuria is the most significant predictor of renal survival in FSGS 5