63 Nephrotic Syndrome
Nephrotic syndrome is defined by an association of the following four clinical and laboratory findings: (1) edema, (2) proteinuria, (3) hypoalbuminemia, and (4) hyperlipidemia. Nephrotic syndrome may be a manifestation of many underlying renal disease processes. Most often in children, however, the nephrotic syndrome is idiopathic, with an incidence of two to seven per 100,000 children younger than 16 years old. Idiopathic nephrotic syndrome can be broadly categorized based on the response to oral steroid treatment (steroid sensitive, steroid dependent, and steroid resistant). The majority of biopsy specimens comprise three underlying histologic lesions: minimal-change nephrotic syndrome (MCNS), focal segmental glomerulosclerosis (FSGS), and membranous nephropathy, the latter being rare in childhood. MCNS is the most common (60%-90% of cases), although there has been an apparent increase in the incidence of FSGS over the past several decades.
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.
Clinical Presentation
Demographic Factors
The clinical and histopathologic distribution of nephrotic syndrome varies by age at onset and race. MCNS typically presents between 2 and 8 years of age (peak, 3 years). About 20% to 30% percent of nephrotic syndrome in adolescence is MCNS. FSGS occurs at a median of 6 years of age and is more common in adolescents than in younger children. MCNS is twofold more common in boys than girls until adolescence when both sexes are equally affected, and its incidence is higher in white and East Asian relative to black children. Steroid-resistant nephrotic syndrome is more common in black and Hispanic children. Genetic syndromes and congenital infections are considerably more common causes of nephrotic syndrome in infancy.
Edema
Edema is the main presenting feature, and its onset may be rapid or insidious. Edema is detectable when fluid accumulation is greater than 3% to 5% of body weight. Edema often presents in the periorbital region, is more pronounced in the morning, and is often misdiagnosed and treated as an allergic reaction or seasonal allergies. Edema may fluctuate with positional changes and activity, with lower extremity swelling being more noticeable over the course of the day. Edema develops in other dependent areas such as the sacral region and genitalia. Pleural effusions are generally asymptomatic but if large may cause respiratory compromise. Ascites may lead to umbilical or inguinal hernias as well as to more serious complications, such as spontaneous bacterial peritonitis (SBP). Bowel wall edema may produce diminished appetite; abdominal colic; and diarrhea, which, if chronic, can lead to a protein-losing enteropathy. Skin breakdown and infection can occur in the setting of severe edema (Figure 63-2).
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