What causes nephrotic syndrome?

Causes 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 the relative frequency varying by age and ethnicity. 1

Primary (Idiopathic) Causes

• Podocytopathies are the most common primary causes of nephrotic syndrome 2:

  • Minimal Change Disease (MCD) - most common cause in children 3, 4
  • Focal Segmental Glomerulosclerosis (FSGS) - most common in adults of African ancestry 3
  • Membranous Nephropathy - most common in white adults 3, 4

• Immunoglobulin and complement-mediated glomerular diseases with an MPGN (membranoproliferative glomerulonephritis) pattern 1

• Pathophysiology: Evidence suggests primary T-cell disorders may be responsible for MCD and FSGS, with a proposed T-cell-driven circulating factor that interferes with glomerular permeability to albumin 1

Secondary Causes

• Systemic diseases:

  • Diabetes mellitus - most common secondary cause in adults 3, 5
  • Systemic lupus erythematosus 2, 4
  • Amyloidosis 2, 4

• Infections:

  • Various infectious agents can trigger infection-related glomerulonephritis 1, 2

• Malignancies:

  • Hematologic malignancies 4
  • Solid tumors can be associated with paraneoplastic glomerular disease 1

• Medication-induced:

  • Certain drugs can cause nephrotic syndrome 2
  • Cancer therapies including targeted agents and immunotherapies may cause podocytopathies 1
    • Anti-angiogenesis drugs are associated with proteinuria and lesions such as minimal change disease/FSGS 1
    • Immune checkpoint inhibitors can cause nephrotic syndrome 1

Autoimmune Mechanisms

• In some primary nephrotic syndromes, autoantibodies against podocyte antigens can be detected 2
• In membranous nephropathy, there is unequivocal proof that it is an autoimmune disease 1
• Anti-phospholipase A2 receptor antibodies are diagnostic of membranous nephropathy 4

Clinical Presentation

• Classic triad: Edema, proteinuria (>3.5 g/day), and hypoalbuminemia (<30 g/L) 3, 5
• Often accompanied by hyperlipidemia 1, 2
• Patients typically present with periorbital edema (morning) or dependent pitting edema (later in day) 3

Complications

• Venous thromboembolism: High risk, especially in membranous nephropathy (renal vein thrombosis 29%, pulmonary embolism 17-28%, deep vein thrombosis 11%) 1, 4
• Increased risk of infection, particularly cellulitis and spontaneous bacterial peritonitis 1
• Accelerated coronary heart disease risk (4x greater than age/sex-matched controls) due to hyperlipidemia, hypertension, and hypercoagulability 1
• Progressive renal damage: Prolonged nephrotic proteinuria can lead to renal scarring and eventual renal failure 1
  • Patients with proteinuria >3.8 g/day have a 35% risk of end-stage renal disease within 2 years 1

Diagnostic Approach

• Confirm nephrotic-range proteinuria with quantitative measurement (protein:creatinine ratio >300-350 mg/mmol) 3
• Kidney biopsy is usually performed to determine the specific histologic variant 3, 6
• In children with typical presentation, a trial of steroids may be attempted before biopsy 4
• In adults with positive anti-phospholipase A2 receptor antibodies, biopsy may be deferred as this confirms membranous nephropathy 4

Understanding the specific cause of nephrotic syndrome is crucial for determining appropriate treatment and prognosis, with management strategies varying based on the underlying etiology 1, 6.