What are the causes of nephrotic syndrome in adults and children?

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 (MN)—with the relative frequency varying by age and ethnicity. 1

Primary (Idiopathic) Causes

The primary glomerular diseases causing nephrotic syndrome differ significantly between children and adults:

In Children

• Minimal Change Disease (MCD) is the most common cause in children under 12 years, accounting for 70-90% of pediatric cases. 2, 3 This is why children under 12 with typical presentation can be treated empirically with glucocorticoids without biopsy. 2, 4
• Focal Segmental Glomerulosclerosis (FSGS) is the second most common primary cause in children. 4, 3

In Adults

• Membranous Nephropathy (MN) is the most common primary cause in white adults, now proven to be an autoimmune disease with pathogenic autoantibodies targeting podocyte antigens (particularly anti-phospholipase A2 receptor). 2, 5
• Focal Segmental Glomerulosclerosis (FSGS) is the most common primary cause in populations of African ancestry and accounts for a significant proportion of adult cases overall. 6, 5
• Minimal Change Disease accounts for approximately 15% of adult idiopathic nephrotic syndrome. 7

The 2021 KDIGO guidelines propose classifying FSGS into four subclasses: Primary FSGS, Genetic FSGS, Secondary FSGS, and FSGS of undetermined cause, which helps guide treatment decisions. 1, 2

Secondary Causes

Secondary causes must be systematically excluded before diagnosing primary nephrotic syndrome, as immunosuppression should not be used in secondary FSGS. 6

Systemic Diseases

• Diabetes mellitus is the most common multisystem disease causing nephrotic syndrome. 5
• Systemic lupus erythematosus, particularly Class V membranous lupus nephritis, is a major secondary cause. 1, 2
• Amyloidosis can present with nephrotic syndrome. 4

Infections

• HIV infection can trigger infection-related glomerulonephritis. 2
• Various other viral infections can cause secondary glomerular disease. 6
• Bacterial infections may be associated with infection-related glomerulonephritis. 8

Malignancies

• Solid tumors can cause paraneoplastic glomerular disease. 1, 2
• Hematologic malignancies are associated with nephrotic syndrome. 4

Medications and Cancer Therapies

• Anti-angiogenesis drugs are associated with proteinuria and lesions such as MCD/FSGS. 1, 2
• Immune checkpoint inhibitors can cause nephrotic syndrome. 1, 2
• Other targeted cancer therapies and immunotherapies may cause podocytopathies. 1, 2
• Drug-induced glomerular injury can manifest as secondary FSGS or membranous nephropathy. 6, 2

Other Secondary Causes

• History of prematurity should be considered as a potential etiology for secondary FSGS due to reduced nephron number. 6
• Immunoglobulin and complement-mediated glomerular diseases with an MPGN pattern can cause nephrotic syndrome. 1

Genetic/Congenital Causes

Genetic testing is now recommended for patients with familial kidney disease, syndromic features, or steroid-resistant FSGS, representing a significant change from prior guidelines. 6, 2

When to Consider Genetic Testing

• Familial kidney disease with family history of nephrotic syndrome. 2
• Syndromic features with extra-renal manifestations. 2
• Steroid-resistant FSGS: 11-24% of adults with steroid-resistant nephrotic syndrome and FSGS on biopsy will have disease-causing variants, primarily in type IV collagen or podocyte genes. 6, 2
• Early-onset disease in young patients. 6, 2

Common Genetic Mutations

• NPHS1, NPHS2, WT1, and PLCE1 are common genetic mutations associated with congenital nephrotic syndrome. 6, 2

Pathophysiological Mechanisms

Understanding the underlying mechanisms helps clarify the causes:

• Podocyte dysfunction is the primary pathophysiological mechanism, leading to increased glomerular permeability to proteins. 6
• T-cell-driven circulating "glomerular permeability factor" has been proposed in MCD and FSGS, suggesting a primary T-cell disorder. 6, 1, 3
• Autoimmune mechanisms are definitively proven in membranous nephropathy, with pathogenic autoantibodies targeting podocyte antigens. 6, 1

Clinical Pitfalls

The most critical pitfall is failing to distinguish primary from secondary causes, as this has profound treatment implications—immunosuppression should not be used in secondary FSGS. 6 Additionally, patients with proteinuria >3.8 g/day have a 35% risk of end-stage renal disease within 2 years, regardless of underlying histology, emphasizing the urgency of accurate diagnosis and appropriate treatment. 6, 1