Treatment of Nephrotic Syndrome

1. General Supportive Measures (all patients)

• Salt and fluid restriction - dietary sodium restriction (~2 g/day) is first-line for edema.
• Diuretics - loop diuretics (furosemide, often at higher doses due to reduced bioavailability and protein binding in nephrotic states) +/- thiazides for diuretic resistance. IV albumin plus diuretic can be used in severe, refractory edema/anasarca, though evidence for routine use is weak.
• ACE inhibitors / ARBs - reduce intraglomerular pressure and proteinuria independent of blood pressure control; standard of care in most proteinuric nephropathies unless contraindicated (hyperkalemia, AKI, pregnancy).
• Statins - to manage the hyperlipidemia that accompanies hypoalbuminemia.
• Anticoagulation - prophylactic anticoagulation is considered in adults with severe hypoalbuminemia (albumin <2.0-2.5 g/dL), especially with membranous nephropathy, given the hypercoagulable state and risk of renal vein thrombosis/pulmonary embolism. This is more relevant in adults than children.
• Infection precautions - increased susceptibility to infection (loss of immunoglobulins in urine); pneumococcal vaccination is often recommended; prompt treatment of infections (historically a major cause of death, especially in children before antibiotics).
• Nutrition - adequate but not excessive protein intake; avoid high-protein diets which can worsen proteinuria.

2. Disease-Specific Immunosuppressive Therapy

• Oral glucocorticoids are first-line and have been standard for over 60 years - typically prednisone 2 mg/kg/day (max 60 mg/day) for 4-8 weeks. About 75% remit within 2 weeks and ~95% by 4 weeks (steroid-sensitive nephrotic syndrome, SSNS).
• Relapses are common; frequently relapsing or steroid-dependent disease may require steroid-sparing agents: levamisole, cyclophosphamide, calcineurin inhibitors (cyclosporine, tacrolimus), mycophenolate mofetil, or rituximab.
• Steroid-resistant nephrotic syndrome (SRNS) - patients failing to remit after 4-8 weeks require renal biopsy and are managed with calcineurin inhibitors as first-line steroid-resistant therapy, with cyclophosphamide, mycophenolate, or rituximab as alternatives. SRNS carries a much higher risk of progression to chronic kidney disease.

• Minimal change disease: corticosteroids first-line (often longer courses than in children); calcineurin inhibitors, cyclophosphamide, or rituximab for steroid-resistant/dependent cases.
• Focal segmental glomerulosclerosis (FSGS): corticosteroids +/- calcineurin inhibitors; rituximab in refractory cases.
• Membranous nephropathy: supportive therapy alone for 6 months is often tried first (spontaneous remission occurs in a subset); if persistent heavy proteinuria or declining function, immunosuppression with rituximab, calcineurin inhibitors, or cyclophosphamide plus corticosteroids (modified Ponticelli regimen).
• Secondary causes (lupus nephritis, diabetic nephropathy, amyloidosis, infections such as HIV/hepatitis B/C, drugs, malignancy): treat the underlying disorder; immunosuppression is tailored to the specific etiology rather than empiric steroids.

Key Point