What are the diagnostic criteria and treatment options for Nephrotic Syndrome (NS)?

Diagnostic Criteria and Treatment of Nephrotic Syndrome

Diagnostic Criteria

Nephrotic syndrome is diagnosed by the classic triad of heavy proteinuria (≥3.5 g/day in adults; ≥1.0 g/m²/day in children), hypoalbuminemia (<3.0 g/dL in adults; <2.5 g/dL in children), and edema. 1, 2

Essential Diagnostic Features

• Proteinuria: Dipstick >3+ or spot protein/creatinine ratio >200 mg/mmol; quantified as ≥3.5 g/day in adults or ≥1.0 g/m²/day in children 1, 2
• Hypoalbuminemia: Serum albumin <3.0 g/dL in adults or <2.5 g/dL in children 1, 2
• Edema: Can be dependent or non-dependent, including ascites, pleural effusions, and scrotal/labial edema 1
• Hypercholesterolemia: Commonly present but not required for diagnosis 1

Initial Diagnostic Workup

Complete blood biochemistry including hemogram, sodium, chloride, albumin, magnesium, creatinine, urea, total proteins, cholesterol, triglycerides, and glucose. 2, 3

• Thyroid function tests (TSH and free T4) and serum IgG levels 2, 3
• Calcium-phosphate metabolism: ionized calcium, phosphate, alkaline phosphatase, PTH, and 25(OH) vitamin D3 2, 3
• Abdominal ultrasound to evaluate kidney echogenicity, size, ascites, and effusions 2, 3
• Cardiac ultrasound to assess for effusions and left ventricular mass 3

Age-Specific Considerations

Atypical features requiring further investigation include age <1 or >12 years at presentation, features of nephritic syndrome (renal impairment, macroscopic hematuria, hypertension), persistent hypertension, persistent renal impairment, or systemic disease features. [@user_context@]

Treatment Approach

Pediatric Patients (Age 1-12 Years)

For children younger than 12 years with presumed minimal change disease, initiate glucocorticoid therapy with prednisolone 60 mg/m²/day in three divided doses for 4 weeks, followed by 40 mg/m²/day as single-dose alternate-day therapy for 4 weeks. 4, 5

• If complete remission occurs (proteinuria <4 mg/m²/h on 3 consecutive days within 7 days), no kidney biopsy is needed 1, 5
• If no response after 4 weeks of daily prednisolone 60 mg/m² plus three methylprednisolone pulses, classify as steroid-resistant and proceed to genetic testing and kidney biopsy 1, 6

Steroid-Resistant Nephrotic Syndrome

For steroid-resistant cases, calcineurin inhibitors (cyclosporine or tacrolimus) are the standard of care, achieving complete or partial remission in approximately 70% of patients with non-genetic disease. 6

• Consider genetic testing before initiating immunosuppression, as genetic forms do not respond to immunosuppressive therapy 3, 6
• One-third of steroid-resistant patients have mutations in podocyte genes 6

Adult Patients

In adults, kidney biopsy is typically indicated for diagnosis before initiating treatment, except when serum anti-phospholipase A2 receptor antibodies are positive, which is diagnostic of membranous nephropathy. 5

• For adults with minimal change disease or focal segmental glomerulosclerosis, initiate prednisone 1 mg/kg/day for >4 months 1
• Complete remission is defined as proteinuria <0.20 g/day with serum albumin >35 g/L 1

Symptomatic Management

Fluid and Edema Control

Restrict dietary sodium as first-line intervention and limit fluid intake when feasible, especially with hyponatremia and severe edema. 2, 3

• Administer furosemide 0.5-2 mg/kg per dose (up to six times daily; maximum 10 mg/kg/day) for patients with intravascular fluid overload and preserved kidney function 1, 2
• Avoid diuretics in patients with evidence of intravascular hypovolemia (prolonged capillary refill time, tachycardia, hypotension, oliguria, abdominal discomfort) 1, 2
• If using potassium-sparing diuretics, prefer amiloride over spironolactone due to direct ENaC activation in nephrotic syndrome 1

Albumin Infusions

Administer intravenous albumin only for clinical indicators of hypovolemia (oliguria, acute kidney injury, prolonged capillary refill, tachycardia, hypotension, abdominal discomfort) or failure to thrive, not based on serum albumin levels. 1, 3

• When indicated, use 1-4 g/kg/day based on clinical response 1
• Consider administering furosemide 0.5-2 mg/kg at the end of albumin infusions unless marked hypovolemia or hyponatremia is present 1, 2

Complication Prevention

Thromboembolism

Monitor for thromboembolism, especially with significant hypoalbuminemia, and consider prophylactic anticoagulation when central venous access is required. 1, 2, 3

• Membranous nephropathy carries particularly high thrombotic risk 5

Infection Prophylaxis

Implement infection prophylaxis measures, especially in severe cases, due to loss of complement and immunoglobulin in urine. 2, 3

• Monitor for spontaneous bacterial peritonitis (abdominal pain, rebound tenderness, fevers) and encapsulated bacterial infections [@user_context@]

Additional Supportive Care

• Supplement with vitamin D (colecalciferol or calcifediol) and calcium 250-500 mg/day for low 25-OH-D3, low ionized calcium, or elevated PTH 2
• Consider statins when LDL cholesterol is persistently elevated with additional cardiovascular risk factors 2
• Monitor and treat iron deficiency; administer erythropoietin for anemia despite iron supplementation 2

Relapse Management

Relapse is defined as proteinuria >3+ for 3 consecutive days (or >3.5 g/day in adults after >1 month of complete remission). [1, @user_context@]

• Frequently relapsing disease (≥2 relapses within 6 months) requires alternative immunosuppressive therapy beyond corticosteroids 1, 5
• Steroid-dependent disease (two consecutive relapses during therapy or within 14 days of completing steroids) necessitates consideration of cyclosporine or other steroid-sparing agents 1

Critical Pitfalls to Avoid

• Never use immunosuppressive agents for genetic forms of nephrotic syndrome—they are ineffective and expose patients to unnecessary toxicity 3
• Do not administer diuretics to hypovolemic patients—assess volume status carefully before initiating diuretic therapy 1, 2
• Avoid furosemide doses >6 mg/kg/day for >1 week and infuse over 5-30 minutes to minimize ototoxicity 1
• Do not delay genetic testing in steroid-resistant cases—one-third have genetic mutations that preclude response to immunosuppression 6