Etiology and Pathogenesis

Although most often idiopathic, a variety of conditions and agents are associated with the nephrotic syndrome. These include (1) infections (e.g., HIV, hepatitis B and C, syphilis, toxoplasmosis, malaria), (2) drugs or toxins (e.g., nonsteroidal antiinflammatory drugs, lithium, ampicillin, penicillamine, heroin, mercury), (3) malignancy (lymphoma, leukemia), (4) allergens (e.g., certain foods and bee stings), and (5) obesity. Nephrotic syndrome may also be an associated feature of several glomerulonephritides, such as lupus nephritis, membranoproliferative glomerulonephritis (MPGN), and immunoglobulin A (IgA) nephropathy. With advances in molecular biology, there has been increasing discovery of genetic disorders resulting in steroid-resistant nephrotic syndrome (Table 63-1). The clinical course and histopathology depend on the underlying disease process or precipitating factors.

The frequent association of both the onset and relapse of “idiopathic” nephrotic syndrome with an antecedent upper respiratory tract infection or atopic event, as well as the response to immunosuppressive therapy, suggests that it is immunologically mediated. Multiple immunologic abnormalities and circulating factors that affect glomerular capillary permeability have been described, but the exact pathophysiology remains to be elucidated. The established familial occurrence (mostly in siblings) and similarity of the clinical course within families also implicate genetic factors.

Although the pathophysiologic mechanisms responsible for nephrotic syndrome clearly involve both environmental and genetic factors and differ based on the underlying diagnosis, the unifying pathology is damage to the glomerular filtration barrier either through injury to the glomerular basement membrane (GBM) or podocytes. On electron microscopy, there is effacement, retraction, and vacuolization of epithelial foot processes, and in the unique case of membranous nephropathy, there are immune complex deposits. Light microscopy may show no abnormalities (minimal change), mesangial proliferation or matrix expansion, any of several morphologic variants of focal and segmental glomerulosclerosis (FSGS), or thickening of the GBM (membranous). Immunofluorescent staining results are typically negative in MCNS. There are characteristic patterns of staining in FSGS and membranous nephropathy as well as in the primary glomerulonephritides associated with nephrotic syndrome, such as lupus and MPGN (Figure 63-1). Although the histopathology is important, particularly if there is significant tubulointerstitial fibrosis and glomerulosclerosis, the response to steroid therapy is the most important predictor of clinical outcome.

Figure 63-1 Pathology of the nephrotic syndrome.

Clinical Presentation