What are the diagnostic and treatment approaches for nephrotic syndrome?

Nephrotic Syndrome Diagnosis

Nephrotic syndrome is diagnosed by the triad of proteinuria exceeding 3.5 g/24 hours (or UPCR ≥2 g/g in children), serum albumin <3.0 g/dL in adults (≤2.5 g/dL in children), and edema, with hyperlipidemia commonly present but not required for diagnosis. 1, 2

Core Diagnostic Criteria

Adults

• Proteinuria ≥3.5 g/24 hours is the threshold for nephrotic-range proteinuria 1, 2
• Serum albumin <3.0 g/dL defines hypoalbuminemia 1, 2
• Edema is typically present as a clinical manifestation 1, 3
• Hyperlipidemia and lipiduria are often present but not required for diagnosis 1, 3

Children

• Proteinuria ≥40 mg/h/m² or first morning UPCR of ≥2 g/g 1, 2
• Serum albumin ≤2.5 g/dL (lower threshold than adults) 1, 2
• Edema is a key clinical feature 1

Important Technical Consideration

• Albumin assay method affects results: A serum albumin of 2.5 g/dL measured with bromocresol green (BCG) equals approximately 2.0 g/dL with bromocresol purple (BCP) or immunonephelometry 1, 2
• Document which assay method was used to avoid misinterpretation 1

Initial Diagnostic Evaluation

Laboratory Assessment

• Quantify proteinuria with 24-hour urine collection or spot urine protein:creatinine ratio (PCR) or albumin:creatinine ratio (ACR) 2
• Complete blood count with platelets 1
• Comprehensive metabolic panel including serum albumin, electrolytes, creatinine, urea, and glucose 2
• Lipid profile (total cholesterol, LDL, HDL, triglycerides) 1
• Complement levels (C3, C4) to assess for immune-mediated disease 1
• Thyroid function tests, serum IgG level, calcium, phosphate, alkaline phosphatase, PTH, and vitamin D levels 1

Screening for Secondary Causes

• Diabetes mellitus screening (fasting glucose, HbA1c) - most common secondary cause in adults 3, 4
• Antinuclear antibody (ANA) and anti-dsDNA if systemic lupus erythematosus is suspected 1
• Hepatitis B and C serologies to identify viral-associated causes 1
• HIV testing in high-risk populations 1
• Medication review to identify nephrotoxic agents (NSAIDs, certain antibiotics) 1
• Serum and urine protein electrophoresis if amyloidosis or multiple myeloma is suspected 1

Imaging Studies

• Renal ultrasound to assess kidney size and echogenicity, particularly before potential biopsy 1
• Abdominal ultrasound to evaluate for ascites 1
• Cardiac ultrasound to check for effusions and left ventricular mass 1

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 (>90%) 1, 2
• Initial treatment with glucocorticoids without biopsy is standard 1, 2
• Kidney biopsy is indicated only for steroid resistance (failure to achieve remission after 4-6 weeks of corticosteroid therapy) 1

Children ≥12 Years and Adults

• Kidney biopsy is recommended to determine the underlying cause before initiating immunosuppressive therapy 1, 2
• Exception: Positive serum anti-phospholipase A2 receptor antibodies are diagnostic of membranous nephropathy and biopsy may not be needed 1
• Perform biopsy within the first month after nephrotic syndrome onset, preferably before starting immunosuppressive treatment 1

Biopsy Technical Requirements

• Sample should include at least 8 glomeruli for light microscopy 1
• Light microscopy stains: 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 is recommended to facilitate recognition of proliferative and membranous lesions 1

Complications Assessment

Thromboembolism Risk

• Assess venous thromboembolism (VTE) risk, particularly when serum albumin falls below 2.9 g/dL 1, 2
• Membranous nephropathy carries higher VTE risk than other causes of nephrotic syndrome 1
• Consider using validated risk assessment tools (e.g., http://www.med.unc.edu/gntools/) 1
• Prophylactic anticoagulation should be considered in high-risk patients, particularly those with membranous nephropathy and serum albumin <2.9 g/dL 1

Infection Risk

• Patients are at increased risk for serious bacterial infections due to loss of immunoglobulins in urine 3, 4
• Monitor for signs of infection, particularly if immunosuppressive therapy is initiated 1

Acute Kidney Injury

• Assess for acute kidney injury at presentation and monitor renal function closely 3, 4
• Spontaneous acute kidney injury from nephrotic syndrome is rare but can occur 3

Special Diagnostic Considerations

Congenital Nephrotic Syndrome (Age <3 Months)

• Perform infectious screening for congenital syphilis (T. pallidum antibodies, TPHA) and congenital CMV (PCR for viral DNA in urine/saliva) 5
• Genetic testing is essential as most cases are caused by genetic abnormalities 5
• Anti-NEP antibody screening should be performed if kidney failure at presentation, transient proteinuria at birth, family history of siblings with congenital membranous nephropathy, or membranous nephropathy on biopsy 5
• Test the mother for NEP antibodies if anti-NEP antibody screening is positive 5

Atypical Presentations Requiring Further Investigation

• Non-nephrotic range proteinuria (<3.5 g/day) with hypoalbuminemia - suspect secondary causes or concurrent liver disease 1
• Nephrotic-range proteinuria but serum albumin >3.0 g/dL - consider alternative diagnoses 1
• Obesity may indicate secondary (maladaptive) FSGS 1
• Familial kidney disease or syndromic features - genetic testing is indicated 1

Common Pitfalls to Avoid

• Do not delay diagnosis waiting for 24-hour urine collection - spot urine PCR is adequate for initial assessment 2
• Do not perform routine prophylactic anticoagulation in all patients - risk-stratify based on serum albumin level and underlying cause 1, 4
• Do not use broad, unguided workup - target testing based on clinical suspicion for secondary causes 1, 4
• Do not biopsy young children (<12 years) at initial presentation unless atypical features are present 1, 2
• Do not forget to document albumin assay method as results vary significantly between methods 1, 2