Nephrotic Syndrome

A condition characterized by severe proteinuria (> 3 g/day), hypoalbuminemia, generalized edema, and susceptibility to infections.

The nephrotic syndrome is as common in the elderly as in young adults but, because edema is characteristic, is often misdiagnosed in the elderly as heart failure. Membranous nephropathy is the most common histologically diagnosed cause of nephrotic syndrome (35%), followed by minimal change disease (16%) and primary amyloidosis (12%).

Etiology

Nephrotic syndrome is due to a severe, prolonged increase in glomerular permeability for protein and may result from primary glomerular disease or systemic disease affecting the glomerulus (see Table 98-1). Causes include diabetic nephropathy, membranous nephropathy, minimal change disease, and amyloidosis.

Diabetic nephropathy: Diabetic nephropathy is the most common cause of nephrotic syndrome in the elderly. Most elderly persons develop diabetic nephropathy from type II diabetes. Native Americans, Hispanics, and blacks have higher rates of diabetic nephropathy than do whites.

Membranous nephropathy: The etiology of membranous nephropathy includes drugs (eg, nonsteroidal anti-inflammatory drugs [NSAIDs], penicillamine), infections (eg, hepatitis B), and systemic disease (eg, lupus erythematosus). About 10% of cases are associated with carcinoma of the lung, colon, or stomach.

Minimal change disease: The etiology of minimal change disease includes T-cell lymphoma, Hodgkin's disease, malaria, schistosomiasis, and NSAID-induced tubulointerstitial nephritis.

Amyloidosis: In primary amyloidosis, the amyloid fibrils deposited in the glomerular capillary loops are light chains with a composition similar to the Bence Jones protein. Patients with plasma cell dyscrasias (eg, multiple myeloma) develop renal lesions similar to those occurring with primary amyloidosis. The amyloid fibrils of secondary amyloidosis, which are associated with chronic inflammatory diseases (eg, rheumatoid arthritis; chronic bone, lung, and urinary tract infections; inflammatory bowel disease), are composed of a nonimmunoglobulin protein deposited similarly in the glomeruli. However, involvement of other organ systems is different from that occurring in primary amyloidosis.

Symptoms and Signs

Early signs of nephrotic syndrome include frothy urine due to proteinuria, anorexia, malaise, puffy eyelids, retinal sheen, and muscle wasting. Anasarca with ascites and pleural effusions may occur.

Focal edema may present as difficulty breathing (from pleural effusion or laryngeal edema), substernal chest pain (from pericardial effusion), scrotal swelling, swollen knees (from hydrarthrosis), and swollen abdomen (from ascites). Usually, the edema is mobile (eg, detected in the eyelids in the morning and in the ankles after ambulation). Edema may mask muscle wasting. Parallel white lines in fingernail beds may be due to subungual edema.

Patients may be hypotensive, normotensive, or hypertensive depending on the degree of angiotensin II production. Oliguria or acute renal failure may develop because of hypovolemia and diminished renal perfusion.

Diagnosis

Diagnosis is suggested by the clinical features and laboratory findings, especially proteinuria > 3 g/day. Diagnosis should include testing for serum antinuclear antibodies (ANA) and double-stranded DNA; antibodies to specific antineutrophil cytoplasmic autoantibodies (p- and c-ANCA); hepatitis B and C and HIV antibodies; cryoglobulins; and complement. Electrophoresis of serum and urine protein and immunoglobulins is also used. Renal biopsy is often needed to make a definitive diagnosis of the underlying cause and should not be avoided because of age alone. In diabetic nephropathy, diagnosis can usually be made clinically from a history of long-standing (15 to 20 years) diabetes mellitus and evidence of diabetic retinopathy; a biopsy is rarely necessary.

Prognosis and Treatment

Prognosis is determined largely by that of the underlying condition. In diabetic nephropathy, once nephrotic-range proteinuria develops, the disease generally progresses to renal failure within 3 to 5 years and eventually requires dialysis.

In diabetic nephropathy, controlling blood pressure slows the rate of deterioration of renal function; the use of angiotensin-converting enzyme inhibitors or angiotensin-II receptor blockers, even in normotensive diabetic patients, promotes efferent arteriolar vasodilatation and decreases glomerular capillary pressure. Intensive efforts to regulate blood glucose levels in young insulin-dependent (type I) diabetics have delayed the onset and slowed the progression of diabetic nephropathy as evidenced by decreased microalbuminuria and macroalbuminuria. It seems reasonable to assume, therefore, that similar aggressive treatment in elderly type II diabetics might produce similar beneficial effects, pending the outcome of new studies. Vigorous treatment of urinary tract infections and avoidance of analgesics (which may cause papillary necrosis), especially in combination, also are warranted.

In membranous nephropathy, the response to corticosteroids and immunosuppressants is variable, but worthy of a trial.

In minimal change disease, the response to corticosteroids and immunosuppressants (eg, cyclophosphamide, chlorambucil) is usually good. Elderly patients tolerate immunosuppressants better than corticosteroids, and the long-term risk of malignancy with immunosuppressants is less of a concern than for younger patients.

In amyloidosis, in most chronic forms of proliferative glomerulonephritis (unless associated with systemic immunologic disease), and in focal sclerosis, there is usually little or no response to corticosteroids and immunosuppressants.