What is the etiology of nephrotic range proteinuria?

Etiology of Nephrotic Range Proteinuria

Nephrotic range proteinuria (≥3.5 g/24 hours in adults) results from either primary glomerular diseases—most commonly minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), and membranous nephropathy (MN)—or secondary causes including diabetes mellitus, systemic lupus erythematosus, infections, malignancies, and medications. 1, 2

Primary Causes

Most Common Primary Glomerular Diseases

The three major histologic variants causing nephrotic syndrome vary by age and ethnicity 2:

• Minimal Change Disease (MCD): Characterized by normal-appearing glomeruli on light microscopy but diffuse podocyte foot process effacement on electron microscopy 1. MCD is the most common cause in children and involves a proposed T-cell-driven circulating "glomerular permeability factor" that interferes with glomerular permselectivity to albumin 1, 2.

• Focal Segmental Glomerulosclerosis (FSGS): The 2021 KDIGO guidelines propose a novel classification dividing FSGS into four subclasses 3:

  • Primary FSGS: Immunologically mediated, characterized by diffuse foot process effacement and nephrotic syndrome (often sudden onset), responsive to immunosuppression 3, 1
  • Genetic FSGS: Familial, syndromic, or sporadic forms with identified genetic mutations 3
  • Secondary FSGS: Caused by viral injury, drug-induced injury, glomerular hyperfiltration, or adaptive changes to reduced nephron number 3
  • FSGS of undetermined cause (FSGS-UC): Segmental foot process effacement with proteinuria but no evidence of secondary causes 3

• Membranous Nephropathy (MN): There is unequivocal proof that MN is an autoimmune disease with pathogenic autoantibodies targeting podocyte antigens, particularly anti-phospholipase A2 receptor (PLA2R) antibodies 1, 2.

Less Common Primary Causes

• Immunoglobulin and complement-mediated glomerular diseases with a membranoproliferative glomerulonephritis (MPGN) pattern can cause nephrotic syndrome 2.

• IgA nephropathy with minimal change features: Patients with mesangial IgA deposition and histologic features consistent with MCD should be treated as MCD 3.

Secondary Causes

Systemic Diseases

• Diabetes mellitus: The most common secondary cause in adults 4
• Systemic lupus erythematosus: Lupus nephritis, particularly Class V (membranous lupus nephritis) 3, 5
• Amyloidosis: Both AL and AA amyloidosis 6, 4

Infections

• Various infectious agents can trigger infection-related glomerulonephritis leading to nephrotic syndrome 2
• Viral infections: Including hepatitis B, hepatitis C, and HIV 2

Malignancies

• Solid tumors can be associated with paraneoplastic glomerular disease 2
• Hematologic malignancies: Including multiple myeloma and lymphomas 6, 4

Medications and Therapies

• Cancer therapies: Targeted agents and immunotherapies may cause podocytopathies 2
• Anti-angiogenesis drugs: Associated with proteinuria and lesions such as minimal change disease/FSGS 2
• Immune checkpoint inhibitors: Can cause nephrotic syndrome 2
• NSAIDs, gold, penicillamine, and other nephrotoxic medications 4

Genetic Factors

• Congenital nephrotic syndrome: Primarily caused by genetic defects in podocytes, with common mutations including NPHS1, NPHS2, WT1, and PLCE1 1
• Genetic testing is recommended for patients with familial kidney disease, syndromic features, or steroid-resistant FSGS 3

Pathophysiological Mechanism

The primary mechanism involves increased glomerular permeability to proteins due to podocyte dysfunction 1. The glomerular filtration barrier consists of endothelial cells with glycocalyx, basement membrane, and podocytes with foot processes and slit membranes 7. Loss of albumin leads to decreased oncotic pressure, causing fluid shift from intravascular to interstitial spaces, resulting in edema 1.

Diagnostic Algorithm for FSGS Classification

For patients with FSGS lesion on biopsy, the 2021 KDIGO guidelines recommend the following approach 3:

If nephrotic syndrome is present (proteinuria >3.5 g/d AND serum albumin <30 g/L):

• Evaluate for underlying causes and exclude secondary forms
• Consider genetic screening where appropriate
• If diffuse foot process effacement is present, classify as likely primary FSGS and consider immunosuppression 3

If nephrotic syndrome is absent (nephrotic-range proteinuria >3.5 g/d but albumin >30 g/L OR proteinuria <3.5 g/d):

• Do not start immunosuppression initially
• Provide supportive therapy and monitor proteinuria and serum albumin
• Evaluate for secondary causes including viral, drug-induced, or adaptive changes 3

Clinical Significance

Patients with proteinuria >3.8 g/day have a 35% risk of end-stage renal disease within 2 years, compared to only 4% risk for those with proteinuria <2.0 g/day 1, 2, 8. This underscores the importance of identifying the underlying etiology to guide appropriate treatment and prevent progression to kidney failure.