What are the diagnostic criteria for nephrotic syndrome?

Diagnostic Criteria for Nephrotic Syndrome

Nephrotic syndrome is diagnosed by the triad of proteinuria ≥3.5 g/24 hours (or spot urine protein-to-creatinine ratio ≥3.5 g/g), serum albumin <3.0 g/dL, and edema. 1, 2

Core Diagnostic Criteria in Adults

The diagnosis requires all three of the following:

• Proteinuria ≥3.5 g/24 hours or spot urine protein-to-creatinine ratio (UPCR) ≥3,500 mg/g (≥3.5 g/g) 1, 3
• Serum albumin <3.0 g/dL 4, 1, 2
• Edema (periorbital in the morning, dependent pitting edema later in the day) 1, 2

Hyperlipidemia and lipiduria are commonly present but not required for diagnosis. 2, 5

Pediatric Diagnostic Criteria

For children, the thresholds differ:

• Proteinuria ≥40 mg/h/m² on timed collection, or first morning UPCR ≥2 g/g 4, 1, 2
• Serum albumin ≤2.5 g/dL (traditional threshold, though the 2021 KDIGO guideline suggests <3.0 g/dL) 4, 1, 2
• Edema 1

Important caveat: The U.S. commentary on KDIGO recommends maintaining the traditional pediatric albumin threshold of ≤2.5 g/dL rather than adopting the higher <3.0 g/dL cutoff, as changing this 50-year standard would complicate comparison with historical clinical trials. 4

Critical Laboratory Considerations

Albumin Assay Variability

Know which assay your laboratory uses, as this significantly affects interpretation:

• Bromocresol green (BCG) overestimates serum albumin in nephrotic syndrome 4
• A serum albumin of 2.5 g/dL measured by BCG equals approximately 2.0 g/dL by bromocresol purple (BCP) or immunonephelometry 1, 2
• This matters critically for thromboembolism risk assessment, where albumin <2.9 g/dL triggers anticoagulation consideration 4

Special Diagnostic Scenario

Nephrotic syndrome can occur without nephrotic-range proteinuria when concurrent liver disease reduces albumin synthesis, allowing a steady state at <3.5 g/24 hours despite severe glomerular permeability defects. 6 In such cases, the diagnosis is still valid if hypoalbuminemia and edema are present with proteinuria >2 g/24 hours. 6

Essential Diagnostic Workup

Initial Laboratory Assessment

Obtain the following at presentation:

• Complete blood count with platelets 4, 1
• Serum albumin (note assay method), electrolytes, creatinine, urea 4, 1, 2
• Lipid profile: total cholesterol, LDL, HDL, triglycerides 4, 1
• Thyroid function tests (TSH, free T4) 4, 1
• Serum IgG level 4, 1
• Calcium, phosphate, alkaline phosphatase, PTH, 25(OH) vitamin D3 4, 1

Secondary Cause Evaluation

Suspect secondary causes when proteinuria is <3.5 g/day with hypoalbuminemia, or when proteinuria is nephrotic-range but albumin >3.0 g/dL. 1 Test for:

• Hepatitis B and C serologies, HIV (especially in high-risk populations) 1
• ANA, anti-dsDNA, complement levels (C3, C4) if systemic lupus erythematosus suspected 1
• Serum and urine immunoelectrophoresis/immunofixation plus serum free light chains in all adults to exclude paraprotein-related disease 1
• Anti-phospholipase A2 receptor antibodies (positive result is diagnostic of membranous nephropathy, potentially avoiding biopsy) 1, 2

Imaging Studies

• Renal ultrasound to assess kidney size, echogenicity, and rule out obstruction 4, 1, 2
• Abdominal ultrasound to evaluate for ascites 4, 1
• Cardiac ultrasound to check for pericardial effusions and left ventricular mass 4, 1

Kidney Biopsy Indications

Adults

Perform kidney biopsy in all adults to determine the underlying cause, except when serum anti-phospholipase A2 receptor antibodies are positive (diagnostic of membranous nephropathy). 1, 2

Timing is critical: Biopsy should be performed within the first month after nephrotic syndrome onset and before starting immunosuppressive treatment to establish histologic diagnosis and guide treatment selection. 1

Children

• Children <12 years: Minimal change disease is most common; initial treatment with glucocorticoids without biopsy is standard 1, 2
• Children ≥12 years: Kidney biopsy is recommended to determine underlying cause 1, 2
• Steroid-resistant cases at any age: Biopsy is indicated 1

Technical Requirements for Biopsy

The specimen must include:

• At least 8 glomeruli for light microscopy with H&E, PAS, Masson's trichrome, and silver stain 1
• Immunofluorescence for IgG, C3, IgA, IgM, C1q, κ and λ light chains 1
• Electron microscopy to facilitate recognition of proliferative and membranous lesions 1

Thromboembolism Risk Assessment

This is a critical and often overlooked complication. Assess risk immediately at diagnosis:

• Serum albumin <2.9 g/dL significantly increases venous thromboembolism (VTE) risk 4, 1
• Membranous nephropathy carries higher VTE risk than other causes 1
• Additional risk factors include: BMI >35 kg/m², heart failure, recent surgery, prolonged immobilization, proteinuria >10 g/day 1

Consider prophylactic full-dose anticoagulation (not just prophylactic dosing) when albumin <20-25 g/L AND additional risk factors are present. 1 Use warfarin with target INR 2-3 (requires frequent monitoring due to fluctuating protein binding), not direct oral anticoagulants, which have unpredictable pharmacokinetics in nephrotic syndrome. 1

Common Diagnostic Pitfalls

• Do not diagnose nephrotic syndrome based on proteinuria alone—the full triad must be present 1, 2
• Do not assume all edema is nephrotic syndrome—exclude heart failure, liver disease, and venous insufficiency 4
• Do not delay biopsy in adults—histologic diagnosis is essential for targeted therapy 1
• Do not use direct oral anticoagulants for VTE prophylaxis or treatment in nephrotic syndrome due to significant albumin binding and urinary losses 1