What is the appropriate work-up and treatment approach for a patient with nephrotic syndrome, considering their demographic and medical history, such as diabetes or systemic lupus erythematosus (SLE)?

Nephrotic Syndrome Work-Up

All adults presenting with nephrotic syndrome require a kidney biopsy to establish the underlying diagnosis, except when serum anti-phospholipase A2 receptor antibodies are positive (diagnostic of membranous nephropathy). 1

Initial Diagnostic Confirmation

Establish the diagnosis by documenting:

• Proteinuria ≥3.5 g/day (via 24-hour urine collection or spot urine albumin-to-creatinine ratio ≥300 mg/g) 1
• Hypoalbuminemia <3.0 g/dL in adults 1
• Peripheral edema (typically periorbital in morning, progressing to dependent edema) 1
• Hyperlipidemia with elevated total cholesterol, LDL-C, and triglycerides 1

Perform urinalysis with microscopy to identify fatty casts or oval fat bodies (characteristic of nephrotic syndrome) and to exclude red blood cell casts that would suggest nephritic syndrome instead 1

Secondary Causes Evaluation

The work-up must systematically exclude secondary causes before considering primary glomerular disease:

Essential Laboratory Tests

• Fasting glucose and HbA1c - diabetes mellitus is the most common secondary cause in adults 2, 3
• ANA, anti-dsDNA, complement levels (C3, C4) - to evaluate for systemic lupus erythematosus 4, 3
• Serum and urine protein electrophoresis with immunofixation - to screen for amyloidosis and paraprotein disorders 5
• Hepatitis B and C serologies, HIV testing - infectious causes 5
• Serum anti-phospholipase A2 receptor antibodies - if positive, diagnostic of primary membranous nephropathy and may obviate need for biopsy 1

Medication Review

Review all medications for potential nephrotoxic agents, particularly NSAIDs, which can cause minimal change disease in adults 4

Malignancy Screening

Age-appropriate cancer screening is warranted, as malignancy can be associated with membranous nephropathy and minimal change disease 4

Kidney Biopsy Indications

Kidney biopsy should be performed within the first month after onset, preferably before starting immunosuppressive treatment 1

Biopsy is essential to:

• Distinguish between minimal change disease, focal segmental glomerulosclerosis, and membranous nephropathy (the most common primary causes in adults) 2, 3
• Identify secondary causes such as lupus nephritis or diabetic nephropathy 3
• Guide immunosuppressive therapy decisions 3
• Provide prognostic information 4

The only exception to mandatory biopsy is positive anti-PLA2R antibodies, which are diagnostic of primary membranous nephropathy 1

Complication Assessment

Thromboembolism Risk Stratification

Assess thromboembolism risk immediately, as this is a critical complication with significant morbidity and mortality implications 4, 1

• Consider prophylactic anticoagulation when serum albumin <2.0 g/dL (20 g/L), especially if persistent or in the presence of anti-phospholipid antibodies 4
• Full anticoagulation is mandatory for documented thromboembolic events 4
• Membranous nephropathy carries particularly high thrombotic risk 1

Cardiovascular Risk Assessment

Evaluate ASCVD risk based on:

• LDL-C, apolipoprotein B, triglyceride, and lipoprotein(a) levels 4
• Presence of hypertension and diabetes 4
• Age and other cardiovascular risk enhancers 4

Initiate statin therapy for persistent hyperlipidemia, aligning statin dosage intensity to ASCVD risk 4

Infection Risk

Monitor for increased infection susceptibility due to urinary immunoglobulin losses and potential immunosuppressive therapy 3

Acute Kidney Injury

Measure serum creatinine and estimate GFR to detect acute kidney injury, which can complicate nephrotic syndrome 3, 6

Monitoring Parameters

Establish baseline and monitor regularly:

• Body weight and blood pressure at each visit 4
• Serum creatinine and eGFR 4
• Serum albumin 4
• Proteinuria (24-hour urine or spot urine protein-to-creatinine ratio) 4
• Complete blood count 4
• Lipid profile 4

Schedule visits every 2-4 weeks initially, then adjust based on clinical response 4

Critical Pitfalls to Avoid

Do not dismiss nephrotic syndrome based solely on normal serum albumin, as early or partial nephrotic syndrome may present atypically 1

Do not delay kidney biopsy in adults - biopsy should occur within the first month to establish diagnosis and guide therapy 1

Do not overlook thromboembolism risk when serum albumin <2.9 g/dL - this requires serious consideration of prophylactic anticoagulation, particularly in membranous nephropathy 1

Do not assume diabetic nephropathy without biopsy confirmation - patients with diabetes can have other glomerular diseases requiring different treatment approaches 4

Do not initiate immunosuppressive therapy before excluding secondary causes - treating primary disease when a secondary cause exists (such as malignancy or infection) can worsen outcomes 3

Initial Supportive Management

While awaiting biopsy results or during diagnostic work-up, initiate supportive care:

• Sodium restriction (<2 g/day) and fluid restriction 3, 6
• Loop diuretics (oral or intravenous if resistant to oral therapy) 3, 6
• ACE inhibitor or ARB therapy for antiproteinuric effect and blood pressure control (target <130/80 mmHg) 4, 7
• Statin therapy for hyperlipidemia management 4

Definitive immunosuppressive treatment decisions should await biopsy confirmation of the underlying diagnosis, as treatment varies significantly between minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and secondary causes 4