Nephrotic Syndrome Diagnosis
Nephrotic syndrome is diagnosed in adults when proteinuria exceeds 3.5 g/24 hours (or UPCR ≥2 g/g) combined with serum albumin <3.0 g/dL and edema; in children, the thresholds are proteinuria ≥40 mg/h/m² (or first morning UPCR ≥2 g/g) with serum albumin ≤2.5 g/dL. 1, 2
Core Diagnostic Criteria
Adults
- Proteinuria: >3.5 g/24 hours or UPCR ≥2 g/g 1, 2
- Hypoalbuminemia: Serum albumin <3.0 g/dL 1, 2
- Edema: Peripheral edema is typically present 2, 3
- Hyperlipidemia: Often present but not required for diagnosis 1, 3
Children
- Proteinuria: ≥40 mg/h/m² or first morning UPCR ≥2 g/g 1, 2
- Hypoalbuminemia: Serum albumin ≤2.5 g/dL 1, 2
- Edema: Present in most cases 2
Critical Technical Note
The albumin assay method significantly affects results: 2.5 g/dL measured by bromocresol green (BCG) equals approximately 2.0 g/dL by bromocresol purple (BCP) or immunonephelometry. 1, 2 Always document which assay was used to avoid misdiagnosis.
Initial Diagnostic Workup
Essential Laboratory Tests
- Urinalysis: Quantify proteinuria with 24-hour urine collection or spot UPCR/ACR 1
- Blood tests: Complete blood count, serum albumin, electrolytes, creatinine, urea, lipid profile, glucose 1, 2
- Complement levels: C3 and C4 to assess for immune-mediated disease 2
- Serologic testing: ANA (if lupus suspected), hepatitis B and C serologies, HIV in high-risk populations 2
Imaging Studies
- Renal ultrasound: Assess kidney size and echogenicity, particularly before potential biopsy 2
- Additional imaging: Consider abdominal ultrasound for ascites and cardiac ultrasound for effusions if clinically indicated 2
Age-Based Approach to Kidney Biopsy
Children <12 Years
Do not perform kidney biopsy at initial presentation. Minimal change disease is the most common cause, and initial treatment with glucocorticoids without biopsy is standard practice. 1, 2 Biopsy is indicated only if steroid-resistant after 4-8 weeks of treatment. 1, 2
Children ≥12 Years and Adults
Kidney biopsy is recommended to determine the underlying cause and guide treatment, with one important exception: adults with positive serum anti-phospholipase A2 receptor antibodies (diagnostic of membranous nephropathy) may not require biopsy. 1, 2
Biopsy Technical Requirements
- Perform within the first month after onset, before starting immunosuppressive treatment 2
- Sample must include ≥8 glomeruli for light microscopy (H&E, PAS, Masson's trichrome, silver stain) 2
- Immunofluorescence for IgG, C3, IgA, IgM, C1q, κ and λ light chains 2
- Electron microscopy to identify proliferative and membranous lesions 2
Evaluation for Secondary Causes
High-Suspicion Scenarios
Suspect secondary causes when:
- Non-nephrotic range proteinuria (<3.5 g/day) with hypoalbuminemia 2
- Nephrotic-range proteinuria but serum albumin >3.0 g/dL 2
Targeted Testing Based on Clinical Context
- Diabetes mellitus: Most common secondary cause in adults; check HbA1c and glucose 4, 5
- Systemic lupus erythematosus: ANA, anti-dsDNA, complement levels 6, 2
- Medication review: Identify nephrotoxic agents (NSAIDs, certain antibiotics) 2, 5
- Malignancy screening: Age-appropriate cancer screening, particularly in membranous nephropathy 7, 5
- Amyloidosis: Consider in older adults with concurrent liver disease or cardiac involvement 8
FSGS-Specific Workup
If FSGS is found on biopsy, classify into primary, genetic, secondary, or undetermined cause: 2
- Genetic testing: Indicated for familial kidney disease, syndromic features, or steroid-resistant FSGS 2
- History of prematurity: Document as potential etiology for reduced nephron number 2
- Obesity assessment: May indicate secondary (maladaptive) FSGS 6
Complications Assessment
Thromboembolism Risk
Venous thromboembolism risk is particularly high when serum albumin <2.9 g/dL, especially in membranous nephropathy. 1, 2, 5 Consider prophylactic anticoagulation in high-risk patients using validated risk assessment tools (www.med.unc.edu/gntools/bleedrisk.html). 6, 2
Anticoagulation recommendations:
- Treatment doses of unfractionated or low-molecular-weight heparin or warfarin are preferred 6
- Factor Xa inhibitors and direct thrombin inhibitors are not recommended due to significant albumin binding and urinary losses 6
- In lupus nephritis with nephrotic syndrome and serum albumin <20 g/L, anticoagulant treatment should be considered 6
Infection Risk
- Screen for latent tuberculosis, hepatitis B and C, HIV, and syphilis before immunosuppression 6
- Rule out Strongyloides in at-risk patients with elevated eosinophils 6
- Monitor for serious bacterial infections, though less common than thromboembolism 4, 5
Acute Kidney Injury
Spontaneous AKI from nephrotic syndrome is rare but can occur from the underlying disease or complications. 4, 5 Monitor serum creatinine and eGFR regularly. 1, 2
Common Diagnostic Pitfalls
Atypical Presentations
Nephrotic syndrome can occur without nephrotic-range proteinuria when concurrent liver disease reduces albumin synthesis, reaching steady state at <3.5 g/24h despite severe glomerular permeability defects. 8 Consider this in patients with hepatic amyloidosis or cirrhosis presenting with severe hypoalbuminemia and edema.
Confounding Comorbidities
Maintain high clinical suspicion in patients with cardiac or hepatic diseases that can cause edema and hypoalbuminemia through different mechanisms. 7 The presence of heavy proteinuria on urinalysis distinguishes nephrotic syndrome from these conditions.
Dihydropyridine Calcium Channel Blockers
Amlodipine and nifedipine exacerbate edema and may increase proteinuria. 6 If proteinuria worsens in a patient on these agents, discontinue before concluding that immunosuppression is necessary.
Monitoring After Diagnosis
- Initial phase: Visits every 2-4 weeks for the first 2-4 months 6, 2
- Each visit: Body weight, blood pressure (including out-of-office measures), eGFR, serum albumin, proteinuria (UPCR or 24-hour collection), urine sediment, complete blood count 6, 2
- Long-term: Lifelong monitoring every 3-6 months for renal and extra-renal disease activity and comorbidities 6, 2