Causes and Treatment of Nephrotic Syndrome
Nephrotic syndrome is primarily caused by three major histologic variants: minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), and membranous nephropathy, with treatment approaches varying based on the underlying cause and patient characteristics. 1
Definition and Clinical Features
- Nephrotic syndrome is characterized by 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
- Hyperlipidemia is commonly present as a compensatory mechanism for the loss of plasma proteins 2
- Patients with nephrotic-range proteinuria >3.8 g/day have a 35% risk of end-stage renal disease within 2 years 2
Primary (Idiopathic) Causes
1. Minimal Change Disease (MCD)
- Most common cause in children 3
- Characterized by normal-appearing glomeruli on light microscopy but diffuse foot process effacement on electron microscopy 1
- Proposed pathophysiology involves a T-cell-driven circulating "glomerular permeability factor" that interferes with glomerular permselectivity to albumin 2
2. Focal Segmental Glomerulosclerosis (FSGS)
- Most common primary cause in adults along with membranous nephropathy 3
- Can be classified into primary FSGS, genetic FSGS, secondary FSGS, and FSGS of undetermined cause 1
- Primary FSGS is characterized by diffuse foot process effacement and nephrotic syndrome, often with sudden onset 1
3. Membranous Nephropathy
- Common primary cause in adults 3
- Involves an autoimmune mechanism with pathogenic autoantibodies targeting podocyte antigens 2
- Can be diagnosed non-invasively with positive serum anti-phospholipase A2 receptor antibodies 3
Secondary Causes
- Diabetes mellitus (most common secondary cause in adults) 3, 4
- Systemic lupus erythematosus 5
- Amyloidosis 5
- Infections (including HIV) 5
- Medications 5
- Malignancies, particularly hematologic 3, 5
- Genetic disorders (especially in congenital nephrotic syndrome) 2
Treatment Approaches
General Management for All Types
- Sodium restriction and diuretic therapy for edema management 5, 4
- Blood pressure control, preferably with angiotensin-converting enzyme inhibitors 5, 4
- Statin therapy for hyperlipidemia 5
- Consider thromboembolism prophylaxis in high-risk patients, particularly those with membranous nephropathy 3
Specific Treatment Based on Histologic Type
1. Minimal Change Disease
- First-line therapy: High-dose corticosteroids 6
- For steroid toxicity or contraindications: Consider cyclosporin 1
- For frequent relapses: Consider cyclophosphamide (12-week course) 1
2. Focal Segmental Glomerulosclerosis (FSGS)
- Treatment should only be considered for idiopathic FSGS with clinical features of nephrotic syndrome 1
- First-line therapy: Prednisone 1 mg/kg/day (maximum 80 mg) or alternate-day dose of 2 mg/kg (maximum 120 mg) 1
- Continue high-dose corticosteroids for a minimum of 4 weeks up to 16 weeks as tolerated or until complete remission 1
- Taper corticosteroids slowly over 6 months after achieving complete remission 1
- For patients with contraindications to steroids (diabetes, psychiatric conditions, severe osteoporosis): Consider calcineurin inhibitors as first-line therapy 1
- Cyclosporine 3-5 mg/kg/day in 2 divided doses OR
- Tacrolimus 0.05-0.1 mg/kg/day in 2 divided doses 1
3. Steroid-Resistant Nephrotic Syndrome
- Calcineurin inhibitors (cyclosporine or tacrolimus) are standard of care for non-genetic forms 7
- Approximately 70% of patients achieve complete or partial remission with calcineurin inhibitors 7
- Additional treatment with renin-angiotensin system inhibitors is recommended for hypertension and reducing proteinuria 7
Special Considerations
- Genetic testing should be considered in early-onset cases or those with family history 1
- A kidney biopsy is usually indicated in adults to determine the specific cause, except when anti-phospholipase A2 receptor antibodies are positive (diagnostic of membranous nephropathy) 3, 5
- In children, a trial of steroids without biopsy is reasonable as initial management due to high prevalence of steroid-responsive minimal change disease 3
- Remission of proteinuria is the most significant predictor of renal survival in FSGS 1