What are the causes of nephrotic syndrome?

Causes of Nephrotic Syndrome

Nephrotic syndrome results from primary glomerular diseases (minimal change disease, focal segmental glomerulosclerosis, and membranous nephropathy) or secondary causes (diabetes mellitus, systemic lupus erythematosus, infections, malignancies, and medications), with the specific etiology varying significantly by age and ethnicity. 1, 2

Primary (Idiopathic) Causes

In Children

• Minimal Change Disease (MCD) is the most common cause in children, characterized by normal-appearing glomeruli on light microscopy but diffuse foot process effacement on electron microscopy 1, 2
• Focal Segmental Glomerulosclerosis (FSGS) is the second most common primary cause in pediatric populations 2

In Adults

• Focal Segmental Glomerulosclerosis (FSGS) is one of the most common primary causes in adults and can be classified into four subclasses: (1) primary FSGS (immunologically mediated), (2) genetic FSGS, (3) secondary FSGS (viral injury, medication-related, or adaptive changes), and (4) FSGS of undetermined cause 3
• Membranous Nephropathy (MN) is the most common primary cause in white adults, with unequivocal proof of an autoimmune mechanism involving pathogenic autoantibodies targeting podocyte antigens (specifically M-type phospholipase A2 receptor) 1, 2, 4
• In populations of African ancestry, FSGS is the most common cause of nephrotic syndrome 4

Secondary Causes

Systemic Diseases

• Diabetes mellitus is the most common secondary cause of nephrotic syndrome in adults overall 2, 5, 4
• Systemic lupus erythematosus can cause secondary membranous nephropathy and other glomerular lesions 2, 4
• Amyloidosis (both AL and AA types) can present with nephrotic syndrome 2, 6

Infections

• Hepatitis B infection is a well-recognized cause, particularly in younger populations with secondary membranous nephropathy 7
• Other viral infections can trigger secondary glomerular disease 3

Malignancies

• Hematologic malignancies (lymphomas, leukemias) are associated with nephrotic syndrome 2
• Solid tumors can cause paraneoplastic glomerular disease 6

Medications

• Drug-induced glomerular injury can manifest as secondary FSGS or membranous nephropathy 3

Genetic Causes

Congenital Forms

• Genetic defects in podocytes are the primary cause of congenital nephrotic syndrome, with common mutations including NPHS1, NPHS2, WT1, and PLCE1 1
• Genetic testing is now recommended for patients with familial kidney disease, syndromic features, or steroid-resistant FSGS, representing a significant change from prior guidelines 3
• In adults with steroid-resistant nephrotic syndrome and FSGS on biopsy, 11-24% will have disease-causing variants primarily in type IV collagen or podocyte genes 3

Pathophysiological Mechanisms

• The primary mechanism involves increased glomerular permeability to proteins due to podocyte dysfunction 1
• In MCD and FSGS, a T-cell-driven circulating "glomerular permeability factor" that interferes with glomerular permselectivity to albumin has been proposed 3, 1
• History of prematurity should be considered as a potential etiology for secondary FSGS due to reduced nephron number 3

Clinical Pitfalls

Common diagnostic errors include:

• Failing to distinguish primary from secondary causes, which has critical treatment implications since immunosuppression should not be used in secondary FSGS 3
• Missing genetic causes in steroid-resistant cases, leading to unnecessary exposure to toxic immunosuppressive therapies 3
• Not recognizing that patients with proteinuria >3.8 g/day have a 35% risk of end-stage renal disease within 2 years, regardless of underlying histology 3, 1