What is the pathophysiology and treatment of nephrotic syndrome?

Pathophysiology and Treatment of Nephrotic Syndrome

Nephrotic syndrome is characterized by proteinuria >3.5g/day, hypoalbuminemia, edema, and hyperlipidemia, with treatment focused on reducing proteinuria through immunosuppression for primary causes while managing complications through supportive care. 1, 2

Pathophysiology

Definition and Clinical Features

• Nephrotic syndrome is defined by proteinuria >3.5g/day, serum albumin <3.0g/dL, peripheral edema, and often hyperlipidemia 1, 2
• In children, nephrotic syndrome is traditionally defined with albumin ≤2.5g/dL, though recent guidelines suggest <3.0g/dL 1
• The syndrome results from severe alteration of the glomerular filtration barrier, allowing proteins (primarily albumin) to be lost in urine 3

Underlying Mechanisms

• Proteinuria occurs due to damage to the glomerular filtration barrier, which consists of podocytes, endothelial cells, and the basement membrane 4
• Prolonged nephrotic proteinuria leads to renal scarring and eventually renal failure, with patients having proteinuria >3.8g/day having a 35% risk of end-stage renal disease within 2 years 1
• Hypoalbuminemia is associated with poor prognosis, with a decrease of 1.0g/dL in serum albumin increasing morbidity by 89% and mortality by 137% 1

Classification

• Primary (idiopathic) causes include:
  • Minimal change disease (MCD)
  • Focal segmental glomerulosclerosis (FSGS)
  • Membranous nephropathy 1, 5
• Secondary causes include:
  • Diabetes mellitus (most common in adults)
  • Viral infections
  • Drug-induced nephropathy
  • Genetic forms 1, 5

Complications

• Thromboembolism: Prevalence includes 29% for renal vein thrombosis, 17-28% for pulmonary embolism, and 11% for deep vein thrombosis 1, 3
• Accelerated coronary heart disease: Risk is four times greater than in age and sex-matched controls 1
• Infections: Particularly cellulitis and spontaneous bacterial peritonitis in children 1
• Malnutrition and growth impairment in children 6

Treatment Approach

General Principles

• Treatment objectives include:
  1. Lowering proteinuria
  2. Reducing frequency of relapses
  3. Protecting kidney function and preventing progression to renal failure 1
• Response of proteinuria to therapy is the main prognostic factor in all histologic variants 1

Supportive Care

• Maintain intravascular euvolemia with diuretics (primarily furosemide 0.5-2mg/kg per dose) for patients with fluid overload and preserved kidney function 6
• Avoid diuretics in patients with evidence of intravascular hypovolemia 6
• Consider albumin infusions followed by furosemide (0.5-2mg/kg) unless marked hypovolemia or hyponatremia is present 6
• Ensure adequate nutrition to prevent malnutrition and support growth, particularly in children 6

Specific Treatment Based on Histologic Type

Minimal Change Disease (MCD)

• First-line treatment: High-dose oral glucocorticoids (prednisone) 1, 7
  • Daily single dose of 1mg/kg (maximum 80mg) or alternate-day dose of 2mg/kg (maximum 120mg)
  • Continue high-dose therapy for at least 4 weeks and until complete remission, maximum of 16 weeks
  • Taper prednisone by 5mg every 1-2 weeks to complete a total duration of 6 months 1
• For frequently relapsing/glucocorticoid-dependent MCD: Consider cyclophosphamide, rituximab, calcineurin inhibitors (CNIs), or mycophenolic acid analogs 1

Focal Segmental Glomerulosclerosis (FSGS)

• Evaluate for underlying causes and exclude secondary forms before initiating immunosuppression 1
• For primary FSGS with nephrotic syndrome:
  • Initial therapy: High-dose corticosteroids for 4-16 weeks, then tapered over 6 months 1
  • For steroid-resistant cases: Consider calcineurin inhibitors (cyclosporine or tacrolimus) 1
  • Alternative options: Mycophenolate mofetil with high-dose dexamethasone 1
• For genetic or secondary FSGS: Immunosuppression is not recommended; focus on supportive care 1, 6

Mechanism of Action of Key Medications

• Cyclosporin (a calcineurin inhibitor):
  • Suppresses immune response by down-regulating transcription of cytokine genes, particularly interleukin-2
  • Inhibits cytokine production from T-helper cells and antigen-presenting cells
  • May have direct anti-proteinuric action through effects on glomerular permeability 1
• Prednisone: FDA-approved to induce diuresis or remission of proteinuria in nephrotic syndrome 7

Special Considerations

• Pediatric patients treated with corticosteroids may experience decreased growth velocity, requiring monitoring of linear growth 7
• Elderly patients should receive cautious dosing of corticosteroids due to increased risk of diabetes mellitus, fluid retention, and hypertension 7
• Genetic testing should be considered in appropriate cases to exclude genetic forms of nephrotic syndrome that won't respond to immunosuppression 1, 6

Management of Complications

• Thromboembolism: Consider anticoagulation for known VTE or high-risk patients 1, 3
• Infections: Implement infection prophylaxis measures, especially in children with congenital nephrotic syndrome 6
• Hyperlipidemia: Consider statin therapy for cardiovascular risk reduction 1
• Growth impairment: Consider growth hormone substitution in affected children 6