What is the most common cause of nephrotic syndrome in adults?

Most Common Cause of Nephrotic Syndrome in Adults

In adults, membranous nephropathy is the most common primary cause of nephrotic syndrome, while diabetes mellitus is the most common secondary cause overall. 1, 2

Primary Causes of Nephrotic Syndrome

• Nephrotic syndrome is primarily caused by three major histologic variants: minimal change disease, focal segmental glomerulosclerosis (FSGS), and membranous nephropathy, with the relative frequency varying by age and ethnicity 1
• In white adults, membranous nephropathy is the most common primary cause 3
• In populations of African ancestry, FSGS is the most common primary cause of nephrotic syndrome 3
• Immunoglobulin and complement-mediated glomerular diseases with an MPGN pattern can also cause nephrotic syndrome 1

Secondary Causes of Nephrotic Syndrome

• Diabetes mellitus is the most common secondary cause of nephrotic syndrome in adults 2
• Various infectious agents can trigger infection-related glomerulonephritis leading to nephrotic syndrome 1
• Solid tumors can be associated with paraneoplastic glomerular disease 1
• 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
• Systemic disorders such as lupus nephritis can present with nephrotic syndrome 3

Pathophysiology Considerations

• Primary T-cell disorders may be responsible for minimal change disease and FSGS, with a proposed T-cell-driven circulating factor that interferes with glomerular permeability to albumin 1
• Membranous nephropathy has been definitively proven to be an autoimmune disease 1
• FSGS is not a disease entity but rather a pattern of injury that can be primary (idiopathic) or secondary to various causes 4
• The 2021 KDIGO guidelines propose a classification of FSGS to help differentiate between primary FSGS (which may respond to immunosuppression) and secondary forms (which typically don't) 5

Clinical Implications and Management Approach

• Renal biopsy is essential to confirm the specific cause of nephrotic syndrome in adults 3
• Treatment approach varies significantly based on the underlying cause 2
• In primary FSGS with nephrotic syndrome, immunosuppression has been shown to improve proteinuria and slow progression to ESRD 5
• Patients with proteinuria >3.8 g/day have a 35% risk of end-stage renal disease within 2 years if left untreated 1
• Complications of nephrotic syndrome include hyperlipidemia, venous thromboembolism, increased risk of infection, and accelerated coronary heart disease 1, 2

Important Diagnostic Considerations

• Nephrotic syndrome is defined by a triad of clinical features: edema, substantial proteinuria (>3.5 g/24 hours), and hypoalbuminemia (<30 g/L) 3
• Proteinuria should be documented by quantitative measurement (urine protein:creatinine ratio >300-350 mg/mmol indicates nephrotic range proteinuria) 3
• Differentiating between primary and secondary forms of nephrotic syndrome is crucial for appropriate treatment selection 4
• Urgent referral to a nephrologist (ideally within 2 weeks) is necessary when nephrotic syndrome is suspected 3