What is the differential diagnosis for nephrotic syndrome in adults and children?

Differential Diagnosis of Nephrotic Syndrome

The differential diagnosis of nephrotic syndrome must be systematically divided into primary (idiopathic) glomerular diseases, secondary causes, and genetic/congenital forms, with the specific etiology varying significantly by age, ethnicity, and clinical presentation. 1, 2

Primary (Idiopathic) Glomerular Diseases

In Children

• Minimal Change Disease (MCD): The most common cause in children under 12 years, accounting for the majority of pediatric cases 3, 2, 4
• Focal Segmental Glomerulosclerosis (FSGS): Second most common primary cause in children 2, 4
• Membranous Nephropathy: Rare in the pediatric population 4

In Adults

• Focal Segmental Glomerulosclerosis (FSGS): Most common primary cause in adults, particularly in populations of African ancestry 2, 5, 6
  • Can be further classified into four subclasses: Primary FSGS (with diffuse foot process effacement and sudden-onset nephrotic syndrome), Genetic FSGS (familial, syndromic, or sporadic), Secondary FSGS (viral, drug-induced, or due to glomerular hyperfiltration), and FSGS of undetermined cause 7, 1
• Membranous Nephropathy (MN): Most common primary cause in white adults, now proven to be an autoimmune disease with pathogenic autoantibodies targeting podocyte antigens 1, 8, 5, 6
• Minimal Change Disease: Requires biopsy confirmation in adults, unlike in children 7

Secondary Causes

Systemic Diseases

• Diabetes Mellitus: The single most common secondary cause overall in adults 2, 5, 6
• Systemic Lupus Erythematosus: Particularly Class V membranous lupus nephritis 1, 5
• Amyloidosis: Important consideration in adults with nephrotic syndrome 2, 5

Malignancy-Related

• Solid Tumors: Can cause paraneoplastic glomerular disease 1
• Hematologic Malignancies: Associated with nephrotic syndrome 2

Infection-Related

• Viral Infections: Various infectious agents can trigger infection-related glomerulonephritis 1, 8
• Congenital Infections: Including syphilis (Treponema pallidum), cytomegalovirus (CMV), toxoplasmosis, hepatitis B, and rubella 7
• HIV: Frequently causes nephropathy with proteinuria in children and adults, though HIV-related congenital nephrotic syndrome has not been described 7

Drug-Induced

• Cancer Therapies: Targeted agents and immunotherapies may cause podocytopathies 1
• Anti-Angiogenesis Drugs: Associated with proteinuria and lesions such as minimal change disease/FSGS 1
• Immune Checkpoint Inhibitors: Can cause nephrotic syndrome 1
• Other Medications: Drug-induced glomerular injury can manifest as secondary FSGS or membranous nephropathy 8

Genetic/Congenital Causes

Genetic Testing Indications

• Familial Kidney Disease: Patients with family history of nephrotic syndrome 1, 8
• Syndromic Features: Patients presenting with extra-renal manifestations 1, 8
• 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 8
• Early-Onset Disease: Consider genetic testing in early-onset cases 8

Common Genetic Mutations

• NPHS1, NPHS2, WT1, and PLCE1: Common genetic mutations in congenital nephrotic syndrome, primarily caused by genetic defects in podocytes 8

Special Considerations

• History of Prematurity: Should be considered as potential etiology for secondary FSGS due to reduced nephron number 8

Diagnostic Algorithm by Age

Children Under 12 Years

• Presumptive MCD: Initial treatment with glucocorticoids without biopsy is standard, as MCD is the most common cause 3
• If Steroid-Responsive: No biopsy needed 2
• If Steroid-Resistant: Proceed with genetic testing and kidney biopsy to determine diagnosis 2

Children Over 12 Years and Adults

• Kidney Biopsy Required: To determine underlying cause, except in cases with positive serum anti-phospholipase A2 receptor antibodies (diagnostic of membranous nephropathy) 3, 2
• Evaluate for Secondary Causes: Comprehensive workup to exclude systemic diseases, infections, malignancies, and drug-induced causes 7, 1
• Consider Genetic Screening: Where appropriate, particularly in familial cases, syndromic features, or steroid-resistant disease 7, 1

Critical Diagnostic Pitfall

Failing to distinguish primary from secondary causes has critical treatment implications, since immunosuppression should not be used in secondary FSGS 8. Clinicians must carefully assess for potential clinical and pathologic clues regarding the cause while monitoring patients closely for worsening proteinuria and kidney function, so that the opportunity to provide appropriate immunosuppressive therapy is not missed in primary disease 7.