What is the diagnosis and management approach for a patient with nephrotic syndrome?

Nephrotic Syndrome: Diagnosis and Management

Diagnosis

Nephrotic syndrome is diagnosed by the clinical triad of massive proteinuria (>3.5 g/24 hours or protein:creatinine ratio >300-350 mg/mmol), hypoalbuminemia (<30 g/L), and edema, typically accompanied by hyperlipidemia. 1, 2

Clinical Presentation

• Edema pattern: Periorbital swelling (most prominent in morning) progressing to dependent pitting edema (ankles, legs) later in the day 1
• Associated symptoms: Fatigue, weight gain, frothy urine 3
• Complications to assess: Signs of thromboembolism (leg swelling, chest pain), infection (fever, focal symptoms), or acute kidney injury (oliguria, rising creatinine) 2, 4

Diagnostic Workup

• Quantify proteinuria: Urine protein:creatinine ratio (PCR) or 24-hour urine collection; PCR >300-350 mg/mmol confirms nephrotic range 1
• Serum albumin: Typically <30 g/L 1
• Lipid panel: Assess for hyperlipidemia 2
• Renal function: Serum creatinine and estimated GFR 4

Etiology Determination

In adults, renal biopsy is typically indicated to establish the underlying cause, except when serum anti-phospholipase A2 receptor antibodies are positive, which is diagnostic of membranous nephropathy. 2

Age-specific common causes:

• Children: Minimal change disease (most common), followed by focal segmental glomerulosclerosis (FSGS) 2
• White adults: Membranous nephropathy (most common primary cause) 1
• Adults of African ancestry: FSGS (most common primary cause) 1
• All adults: Diabetes mellitus (most common secondary cause) 4

Secondary cause screening (selective testing based on clinical suspicion):

• Diabetes: Hemoglobin A1c, fasting glucose 4
• Systemic lupus erythematosus: ANA, anti-dsDNA, complement levels 1
• Amyloidosis: Serum/urine protein electrophoresis, free light chains 1
• Infections: HIV, hepatitis B/C serologies 2
• Malignancy: Age-appropriate cancer screening 2

Pediatric-Specific Approach

In children <12 years, empiric glucocorticoid therapy should be initiated without biopsy, as minimal change disease is presumed. 2 Kidney biopsy and genetic testing are reserved for steroid-resistant cases 2

Management

Immediate Symptomatic Treatment

All patients require dietary sodium restriction (<2 g/day), loop diuretics for edema control, and ACE inhibitors or ARBs for antiproteinuric effect. 4

Diuretic Therapy

• First-line: Furosemide 0.5-2 mg/kg per dose (oral or IV), up to 6 times daily, maximum 10 mg/kg/day 5, 6
• Administration: Infuse IV doses over 5-30 minutes to minimize ototoxicity 5, 7
• High-dose caution: Doses >6 mg/kg/day should not exceed 1 week duration due to ototoxicity risk 5, 7
• Alternative loop diuretics: Torsemide or bumetanide may have better oral bioavailability in patients with intestinal edema 5, 8
• Combination therapy for resistance: Add thiazide (metolazone) or epithelial sodium channel blocker (amiloride, NOT spironolactone) 5, 8

Amiloride is preferred over spironolactone as a potassium-sparing diuretic because plasmin in nephrotic urine directly activates the epithelial sodium channel independent of mineralocorticoid receptors. 5, 8

Albumin Infusions

• Indications: Clinical hypovolemia (oliguria, acute kidney injury, prolonged capillary refill, tachycardia, hypotension, abdominal discomfort) or failure to thrive—NOT based on serum albumin levels alone 5
• Dosing with furosemide: Administer furosemide bolus (0.5-2 mg/kg) at the end of each albumin infusion unless marked hypovolemia or hyponatremia present 5, 6
• Contraindications: Avoid in intravascular volume overload without hypovolemia 5

Antiproteinuric Therapy

• ACE inhibitors or ARBs: Reduce proteinuria via dose-dependent mechanism; use if blood pressure tolerates 5
• Combination therapy: ACE inhibitor alone is as effective as ACE inhibitor plus indomethacin for increasing serum albumin 5

Monitoring Requirements

Close monitoring must include fluid status, electrolytes (particularly potassium and sodium), blood pressure, and renal function (urine output and eGFR). 6, 7

Disease-Specific Treatment

Minimal Change Disease (Children)

• Initial therapy: Glucocorticoids for children <12 years 2
• Steroid-responsive: No biopsy needed if remission achieved 2
• Steroid-resistant or frequent relapses: Consider alternative immunosuppression (calcineurin inhibitors, mycophenolate mofetil, rituximab) 3

Adult Primary Nephrotic Syndrome

• Corticosteroids: May benefit some adults, though data are limited 4
• Steroid-resistant disease: Requires alternative immunosuppression 2
• Membranous nephropathy: Consider immunosuppression based on risk stratification 2

Congenital Nephrotic Syndrome

Before considering immunosuppression, comprehensive genetic testing, infection screening, and kidney biopsy (excluding diffuse mesangial sclerosis) must be completed. 5

• Infection-associated: Treat with specific antimicrobials 5
  • Congenital syphilis: Penicillin G (50,000 U/kg IV every 12h if ≤1 week old, every 8h if >1 week, every 6h if >1 month) or benzathine penicillin G (50,000 U/kg IM daily for 10-15 days) 5
  • Congenital CMV: Ganciclovir (6 mg/kg every 12h for 15-21 days) followed by valganciclovir (15 mg/kg every 12h for 6 weeks) 5
• Anti-NEP antibody-mediated: Mainly symptomatic management; screen mother for NEP antibodies 5

Complication Prevention

Thromboembolism

• High-risk patients (particularly membranous nephropathy): Consider prophylactic anticoagulation 2
• Central venous access: If required, administer prophylactic anticoagulation for duration of line placement 5
• General population: Prophylactic anticoagulation not routinely recommended 4

Infection

• Prophylactic antibiotics are not currently recommended 4
• Maintain high index of suspicion for bacterial infections 4

Referral Criteria

Urgent referral to nephrology (within 2 weeks) is necessary for all new cases of nephrotic syndrome. 1 Children with congenital nephrotic syndrome require immediate referral to specialized pediatric nephrology units 5

Common Pitfalls

• Avoid: Intravenous fluids and saline in congenital nephrotic syndrome; use concentrated oral fluids instead 5
• Avoid: Central venous lines when possible due to high thrombosis risk 5
• Avoid: Furosemide in patients with marked hypovolemia, anuria, or severe hyponatremia 6, 7
• Avoid: Spironolactone as potassium-sparing diuretic; use amiloride instead 5
• Monitor: Creatinine increases >0.3 mg/dL indicate significant deterioration and nearly triple in-hospital mortality risk 6