Essentials of Diagnosis and General Considerations
- Edema
- Proteinuria >3.5 g/day
- Hypoalbuminemia <3 g/dL
- Hyperlipidemia: cholesterol >300 mg/100 mL
- Lipiduria: free fat, oval fat bodies, fatty casts
Because treatment and prognosis vary with the cause of nephrotic syndrome, renal biopsy is important. Light microscopy, electron microscopy, and immunofluorescence identification of immune mechanisms diagnose most causes of nephrosis.
Glomerular diseases associated with nephrosis include the following:
Minimal Glomerular Lesions
Minimal-change nephropathy (nil disease) accounts for about 20% of cases of nephrosis in adults and 90% in children. No abnormality is visible by examination of biopsy material with the light microscope. With the electron microscope, alterations of the GBM, with effacement of foot processes of the epithelial cells, are evident. There is no evidence of immune disease by immunofluorescence studies. The response to treatment with corticosteroids is good, but for patients who have frequent relapses with steroids or are steroid resistant, a course of cyclophosphamide or chlorambucil may induce a prolonged remission.
Patients who do not respond to these agents may show a favorable response with cyclosporine or tacrolimus. Renal function usually remains stable.
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Focal Glomerulosclerosis
Focal glomerulosclerosis is the second most common cause of nephrotic syndrome in children and an increasing cause of the nephrotic syndrome in adults. The diagnosis is based on light microscope findings of segmental hyalinosis and sclerosis associated with effacement of the foot processes on electron microscopy. Focal glomerulosclerosis is frequently idiopathic but can be associated with human immunodeficiency virus infection and heroin use. A secondary form of focal glomerulosclerosis without the diffuse changes in foot processes may occur in patients with a solitary kidney, hyperfiltration syndromes, and reflux nephropathy. There are reports of familial variants. The response of the idiopathic form of focal glomerulosclerosis to therapy is suboptimal. Prolonged corticosteroid therapy produces remission in approximately 40% of patients.
Over a 10-year period, approximately 50% of patients will have chronic renal failure. Idiopathic focal glomerulosclerosis has a recurrence rate of 25% after transplantation.
Membranous Nephropathy
Examination of biopsy material with the light microscope shows thickening of the glomerular cells but no cellular proliferation. With the electron microscope, irregular lumpy deposits appear between the basement membrane and the epithelial cells, and new basement membrane material protrudes from the GBM as spikes or domes.
Immunofluorescence studies show diffuse granular deposits of Ig (especially IgG) and complement (C3 component). As the membrane thickens, glomeruli become sclerosed and hyalinized.
The pathogenesis of most cases of membranous nephropathy in humans is unclear. Several mechanisms have been suggested. They include trapping of circulating immune complexes or binding of an antibody to scattered glomerular antigens (either present already or “planted” after a nonrenal-source antigen lodges in the glomerulus).
There is considerable controversy regarding the effectiveness of therapy with steroids or immunosuppressive agents. Therapy should be most often used in patients at high risk of progressive renal failure with the following criteria: proteinuria >5 g/day, hypertension, and elevated serum creatinine.
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Membranoproliferative Glomerulonephritis-Type I and Type II
In type I MPGN, light microscopy shows thickening of glomerular capillaries, accompanied by mesangial proliferation and obliteration of glomeruli. With the electron microscope, subendothelial deposits and growth of mesangium into capillary walls are demonstrable. Immunofluorescence studies show the presence of the C3 component of complement and, rarely, the presence of Ig. The most common cause of MPGN type I is chronic hepatitis C virus infection.
This condition is usually associated with high levels of IgG/IgM. Cryoimmunoglobulins may be present with normal or slightly reduced levels of complement. There is no known effective treatment.
Type II MPGN is characterized by dense deposits visible by electron microscopy and lack of findings by immunofluorescence studies. Treatment is unsatisfactory, and there is a high rate of recurrence after kidney transplantation.
Miscellaneous Diseases
Many medical illnesses that are metabolic, autoimmune, or infectious, as well as neoplastic diseases and reactions to drugs and other toxic substances can produce glomerular disease. These include diabetic glomerulopathy, systemic lupus erythematosus, ANCA-positive renal disease (including Wegener’s granulomatosis), amyloid disease, multiple myeloma, lymphomas, carcinomas, syphilis, reaction to toxins, reaction to drugs (eg, trimethadione), and exposure to heavy metals.
A rare glomerular illness has been recently described with nephrotic syndrome: fibrillary and immunotactoid glomerular nephritis. The lesions of fibrillary glomerulonephritis are characterized by randomly oriented fibril deposits 10-30 nm in diameter located within the mesangium and capillary wall. Immunotactoid glomerulopathy is characterized by deposits of microtubular structures of 18-19 nm and has been associated with lymphoproliferative disorders.
In contrast to amyloid, the deposits in both diseases are Congo red-negative. Treatment is generally unsatisfactory.
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