What laboratory tests and treatment are recommended for a patient presenting with nephrotic syndrome?

Laboratory Evaluation and Treatment for Nephrotic Syndrome

Initial Diagnostic Laboratory Tests

The essential laboratory workup for nephrotic syndrome includes quantifying proteinuria, measuring serum albumin, assessing kidney function, and evaluating lipid levels to confirm the diagnosis and guide management. 1

Core Diagnostic Labs

• Proteinuria quantification: Obtain 24-hour urine collection in adults (diagnostic threshold >3.5 g/24 hours) or first morning urine protein-to-creatinine ratio (UPCR ≥2 g/g in children, PCR >300-350 mg/mmol in adults) 1, 2
• Serum albumin: Measure to confirm hypoalbuminemia (<3.0 g/dL in adults, ≤2.5 g/dL in children); note the assay type used (bromocresol green vs. bromocresol purple) as results vary 1
• Complete blood count with platelets: Essential for baseline assessment and monitoring for complications 1
• Comprehensive metabolic panel: Including serum electrolytes, BUN, creatinine, and eGFR calculation using CKD-EPI equation in adults or modified Schwartz equation in children 1, 3
• Lipid profile: Assess for hyperlipidemia (total cholesterol, LDL-C, HDL-C, triglycerides, apolipoprotein B, and lipoprotein(a)) 4, 1

Secondary Cause Evaluation

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

• Hepatitis B and C serologies: Screen for viral-induced glomerular disease 4, 1
• HIV testing: Particularly in high-risk populations, as HIV-associated nephropathy can present as nephrotic syndrome 4, 1
• Antinuclear antibody (ANA) and anti-dsDNA: If systemic lupus erythematosus is suspected 4, 1
• Complement levels (C3, C4): To assess for immune-mediated disease 4, 1
• Serum and urine immunoelectrophoresis/immunofixation plus serum free light chains: For all adults to exclude paraprotein-related disease 4
• Fasting glucose and HbA1c: To screen for diabetic nephropathy 1
• Anti-phospholipase A2 receptor (PLA2R) antibodies: Positive results are diagnostic of primary membranous nephropathy in adults, potentially obviating the need for biopsy 1, 5

Additional Specialized Testing

• Thyroid function tests: Assess for hypothyroidism secondary to urinary loss of thyroid-binding proteins 1
• Serum IgG level: Often decreased due to urinary losses 1
• Calcium, phosphate, alkaline phosphatase, PTH, and vitamin D levels: Evaluate for mineral bone disease 1

Imaging Studies

• Renal ultrasound: Assess kidney size and echogenicity; particularly important before potential biopsy 1
• Abdominal ultrasound: Evaluate for ascites if clinically indicated 1

Kidney Biopsy Indications

In adults, kidney biopsy should be performed within the first month after nephrotic syndrome onset, preferably before starting immunosuppressive treatment, unless anti-PLA2R antibodies are positive. 1, 5

Biopsy Requirements

• Minimum 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

Pediatric Biopsy Considerations

• Children <12 years: Initial empiric glucocorticoid treatment without biopsy is standard, as minimal change disease is most common 1
• Biopsy indicated for steroid resistance, age ≥12 years, or atypical features 1

Risk Stratification for Complications

Thromboembolism Risk Assessment

Prophylactic anticoagulation should be considered when serum albumin falls below 2.0-2.5 g/L, particularly in membranous nephropathy which carries the highest thromboembolism risk. 4, 1

High-risk features warranting prophylactic anticoagulation include: 4

• Serum albumin <20-25 g/L AND any of the following:
  • Proteinuria >10 g/day
  • Body mass index >35 kg/m²
  • Heart failure (NYHA class III or IV)
  • Recent orthopedic or abdominal surgery
  • Prolonged immobilization
  • Membranous nephropathy (particularly high risk)

Treatment Approach

Supportive Care (All Patients)

• Sodium restriction: Limit dietary sodium to reduce edema 6
• Diuretics: Furosemide 0.5-2 mg/kg per dose for fluid overload with preserved kidney function; avoid in intravascular hypovolemia 3
• RAS inhibition: ACE inhibitors or ARBs to reduce proteinuria and blood pressure 4, 6
• Statin therapy: Consider for persistent hyperlipidemia, particularly with other cardiovascular risk factors; align intensity to ASCVD risk 4

Anticoagulation Management

For documented thromboembolic events, full-dose anticoagulation is required for 6-12 months and/or duration of nephrotic syndrome. 4

• Warfarin remains the anticoagulant of choice with long-term experience; target INR 2-3 with frequent monitoring as protein binding fluctuates with changing albumin 4
• Heparin dosing may require higher than usual doses due to antithrombin III urinary loss 4
• Factor Xa inhibitors and direct thrombin inhibitors are NOT recommended due to significant albumin binding (apixaban 92-94%, rivaroxaban 92-95%) and lack of pharmacokinetic studies in nephrotic syndrome 4, 1

Disease-Specific Immunosuppression

Treatment depends on the underlying histologic diagnosis and classification into primary, genetic, secondary, or undetermined cause. 1

Minimal Change Disease

• First-line: Glucocorticoids (prednisone 1 mg/kg/day, maximum 80 mg) 7
• Alternative: Cyclosporin for steroid-resistant or steroid-dependent cases 4, 7

Focal Segmental Glomerulosclerosis (Primary)

• First-line: Prednisone 1 mg/kg/day (maximum 80 mg) or alternate-day 2 mg/kg (maximum 120 mg) for minimum 4 weeks up to 16 weeks 7
• Taper slowly over 6 months after achieving complete remission 7
• Second-line (steroid-resistant/dependent): Calcineurin inhibitors (cyclosporin 2-4 mg/kg/day, tacrolimus), rituximab, or mycophenolate mofetil 4, 7
• Genetic testing indicated for familial disease, syndromic features, or steroid resistance 1, 7
• AVOID immunosuppression in genetic or secondary FSGS 1, 7

Cyclosporin Dosing Specifics

• Starting dose: 2 mg/kg/day in divided doses, gradually increase to maximum 4-6 mg/kg/day based on pharmacokinetic monitoring 4
• Duration: Continue for minimum 6 months; taper slowly by 0.5 mg/kg/month after complete remission, maintain for 1-2 years 4
• Monitoring: Watch for hypertension, gum hypertrophy, hypertrichosis, and nephrotoxicity 4

Adjunctive Therapy for CKD Progression

For patients with eGFR ≥20 mL/min/1.73 m² and UACR ≥200 mg/g, add SGLT2 inhibitors on top of maximally tolerated RAS inhibition for kidney protection. 7

• Monitor for initial eGFR dip of 3-5 mL/min/1.73 m² in first 4 weeks (reversible, not an indication to discontinue) 7
• Hold during acute illness with nausea, vomiting, or diarrhea to prevent ketoacidosis 7
• Reduce diuretic doses before initiating to prevent hypovolemia 7

Common Pitfalls to Avoid

• Do not use Factor Xa inhibitors or direct thrombin inhibitors for anticoagulation in nephrotic syndrome due to unpredictable pharmacokinetics from heavy protein binding and urinary losses 4, 1
• Do not give immunosuppression for genetic or secondary FSGS—genetic testing and thorough secondary cause evaluation are critical before starting treatment 1, 7
• Do not delay biopsy in adults beyond one month or after starting immunosuppression, as this obscures histologic diagnosis 1
• Do not overlook thromboembolism risk when albumin drops below 2.5 g/dL, especially in membranous nephropathy 4, 1
• Monitor warfarin INR frequently as protein binding fluctuates with changing serum albumin levels 4