Nephrotic Syndrome Causes and Complications

Primary Causes

Nephrotic syndrome is primarily caused by three major histologic variants: minimal change disease, focal segmental glomerulosclerosis, and membranous nephropathy, with the relative frequency varying by age and ethnicity 1, 2
Immunoglobulin and complement-mediated glomerular diseases with an MPGN pattern can cause nephrotic syndrome 1
Primary T-cell disorders may be responsible for minimal change disease and focal segmental glomerulosclerosis, with a proposed T-cell-driven circulating factor that interferes with glomerular permeability to albumin 3, 4

Various infectious agents can trigger infection-related glomerulonephritis 1
Solid tumors can be associated with paraneoplastic glomerular disease 5
Cancer therapies, including targeted agents and immunotherapies, may cause podocytopathies 5
Anti-angiogenesis drugs are associated with proteinuria and lesions such as minimal change disease/FSGS 5
Immune checkpoint inhibitors can cause nephrotic syndrome 5

Often accompanied by hyperlipidemia 2
Patients with nephrotic syndrome are at high risk of venous thromboembolism, especially in membranous nephropathy 4
Increased risk of infection, particularly cellulitis and spontaneous bacterial peritonitis 4
Accelerated coronary heart disease risk due to hyperlipidemia, hypertension, and hypercoagulability 4
Prolonged nephrotic proteinuria can lead to renal scarring and eventual renal failure 4
Patients with proteinuria >3.8 g/day have a 35% risk of end-stage renal disease within 2 years 4
In membranous nephropathy, there is unequivocal proof that it is an autoimmune disease 1

The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines propose a novel classification dividing Focal Segmental Glomerulosclerosis (FSGS) into four subclasses, including Primary FSGS, Genetic FSGS, Secondary FSGS, and FSGS of undetermined cause (FSGS-UC), which can help guide treatment and management of the disease 6, 7
Patients with IgA nephropathy and minimal change features should be treated as Minimal Change Disease (MCD) 8

Systemic lupus erythematosus, particularly Class V (membranous lupus nephritis), can cause nephrotic syndrome 9

The 2021 KDIGO guidelines recommend evaluating patients with FSGS lesion on biopsy for underlying causes, excluding secondary forms, and considering genetic screening where appropriate 7
For patients with nephrotic syndrome and diffuse foot process effacement, the guidelines suggest classifying as likely primary FSGS and considering immunosuppression 7

Genetic testing is recommended for patients with familial kidney disease, syndromic features, or steroid-resistant FSGS 6