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General Considerations
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Nephrotic syndrome may appear as a primary (idiopathic) renal disease or occur in association with any of a number of systemic conditions and hereditary diseases. The most common primary glomerular diseases include membranous nephropathy, focal segmental glomerular sclerosis, minimal change, and membranoproliferative glomerulonephritis (MPGN). In the United States, diabetes mellitus is the most common cause of nephrotic syndrome. Approximately one-third of patients with both type 1 and type 2 diabetes mellitus of at least a 25-year duration will develop nephrotic syndrome, predictably leading to renal failure. Other systemic diseases that may lead to the nephrotic syndrome include systemic lupus erythematous (SLE), amyloidosis, and leukemia.
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Nephrotic syndrome generally reflects noninflammatory damage to the glomerular capillary wall. The underlying glomerular disease results in proteinuria, which occurs from alterations in the charge or size selectivity of the glomerular capillary wall. This increases glomerular permeability to plasma proteins. Albumin is the principal urinary protein lost, but other plasma proteins lost in the urine include hormone-carrying proteins such as vitamin D-binding protein, transferrin, and clotting inhibitors.
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We do not know how to prevent primary nephrotic syndrome. Secondary nephrotic syndromes can often be improved and sometimes completely reversed by treating and controlling the underlying disease.
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Nephrotic syndrome can present with a spectrum of findings ranging from asymptomatic proteinuria to the most common presentation of edema. Edema occurs initially in areas of high intravascular hydrostatic pressure such as in the feet and ankles as well as in areas in which tissue hydrostatic pressure is lowest such as the periorbital and scrotal areas. If the edema is severe and generalized it can present as anasarca.
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Urine dipstick often demonstrates 3+ to 4+ protein and 24-hour urine collection with >3.5 g protein/1.73 m2. Proteinuria can also be estimated from a single urine specimen by calculating the ratio of total urine protein in mg/dL to urine creatinine in mg/dL. This ratio approximates the actual 24-hour protein excretion in grams per day per 1.73 m2 body surface area. Typically the urine sediment has few cells or casts. Urinary lipid may be present in the sediment. It may be entrapped in casts, free in the urine, or enclosed in the plasma membrane of degenerated epithelial cells known as oval fat bodies. Under polarized light, the lipid in oval fat bodies appears as “Maltese crosses” (Figure 23–1).
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Fundamental laboratory abnormalities in nephrotic syndrome include decreased serum albumin (<3 g/dL), decreased total serum protein (<6 g/dL), and hyperlipidemia. Patients may have elevations in their blood urea nitrogen (BUN) and creatinine, but the glomerular filtration rate (GFR) can be normal. Some patients may also manifest anemia, elevated erythrocyte sedimentation rate (ESR), hypocalcemia, and vitamin D deficiency. Other less common laboratory tests may be indicated depending on the patient's clinical presentation. These may include serum protein electrophoresis (SPEP) and urine protein electrophoresis (UPEP) to evaluate for myeloma or amyloidosis, and antinuclear antibody (ANA) to evaluate for SLE. Other tests might include hepatitis serologies, syphilis serology, HIV, complements, cryoglobulins, and thyroid function tests.
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Indications for and benefits of a renal biopsy remain controversial. Nevertheless, it is the standard procedure for determining the cause of proteinuria in adults. Biopsy is often recommended when the etiology of nephrotic-range proteinuria is in doubt, prior to beginning cytotoxic drugs, when the presence of multiple diseases contributing to the clinical picture confounds the diagnosis, or if the patient's clinical course differs from the expected. In general, renal biopsy may be used to aid in management decisions, for example, whether to discontinue therapy because of lack of salvageable renal parenchyma.
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Differential Diagnosis
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The differential diagnosis in nephrotic syndrome can be narrowed significantly based on the patient's age, race, and urine evaluation. For example, minimal change accounts for the majority of cases in children. In adults worldwide, membranous nephropathy and focal glomerulosclerosis are among the commonest causes of primary nephrotic syndrome. In adults over the age of 50 years, membranous nephropathy is the most common cause of idiopathic nephrotic syndrome while focal glomerulosclerosis is the most common cause in African-Americans. Overall, about 50% of patients with nephrotic syndrome have a secondary cause, with the majority of these being secondary to diabetic nephropathy.
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Numerous alterations in lipid profiles occur in the nephrotic syndrome as a result of increased synthesis and decreased catabolism of individual lipid fractions. These include hypercholesterolemia, hypertriglyceridemia, and increased low-density protein (LDL) and very low-density protein (VLDL). These abnormalities may possibly contribute to accelerated atherosclerosis.
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Several abnormalities of the coagulation system occur in nephrotic syndrome. These abnormalities include urinary losses of antithrombin III, proteins C and S, and factors IX, XI, and XII. In addition, plasma fibrinogen, tissue plasminogen activator, and platelet aggregability are all increased. These aberrations lead to an increased incidence of venous and arterial thromboemboli, especially deep venous thrombosis, pulmonary embolism, and renal vein thrombosis. Renal vein thrombosis is most common in membranous nephropathy, with as many as 20–40% of patients affected.
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Vitamin D Deficiency and Hypocalcemia
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Vitamin D-binding protein is a relatively small protein (59 kDa) that is readily filtered and hence lost in the urine. 25-Hydroxyvitamin D, which is bound to vitamin D-binding protein, is also lost in the urine in nephrotic syndrome.
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Patients with nephrotic syndrome have urinary losses of immunoglobulins and defects in the complement cascade. This results in a higher susceptibility to infection, especially with encapsulated organisms such as Streptococcus pneumoniae. In addition, the immunosuppressive medications often used to treat the underlying glomerulopathy contribute to the increased risk of infection in these patients.
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Serum levels of albumin are low in hypoalbuminemia secondary to both losses in the urine and increased albumin catabolism.
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Prolonged and massive proteinuria may culminate in malnutrition as a result of negative nitrogen balance with loss of lean body mass.
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Urinary losses of erythropoietin (30 kDa) and transferrin may lead to an iron-resistant microcytic hypochromic anemia. If renal function deteriorates to the point of chronic kidney disease decreased erythropoietin production may play a role as well.
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Underlying Systemic or Renal Disease Immunosuppressive Medications
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Medications such as corticosteroids may be used for diseases such as minimal change disease and focal glomerular sclerosis. Other treatments may consist of antimicrobial agents such as those for the treatment of secondary syphilis, chemotherapy or tumor resection for nephrotic syndrome associated with malignancy, or simply discontinuing an offending medication such as nonsteroidal anti-inflamatory drugs (NSAIDs) or phenytoin.
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Complications of the Nephrotic Syndrome
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Premature atherosclerosis and anincreased incidence of myocardial infarction have been reported in patients with the nephrotic syndrome. In addition, hyperlipidemia is likely a separate risk factor for both atherosclerotic cardiovascular disease as well as for the progression of renal disease. Hyperlipidemia typically improves after the resolution of the nephrotic syndrome. All lipid-lowering medications have been used in nephrotic syndrome to help reduce the rate of adverse coronary events. The most potent agents are the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors alone or in combination with bile acid sequestrants such as cholestyramine.
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Nephrotic syndrome results in primary renal sodium retention. This may result in peripheral and periorbital edema and, if severe and generalized enough, may result in anasarca with serous effusions. Goals of treatment include salt restriction and use of loop diuretics to achieve slow resolution of edema; rapid diuresis can result in hypovolemia and hypotension. Occasionally, thiazide diuretics must be added to the loop diuretics in order to block sodium reabsorption at multiple sites in the nephron.
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Anticoagulation is indicated in patients with nephrotic syndrome and documented thrombotic events. Anticoagulation is usually continued until the patient experiences resolution of the nephrotic syndrome. Prophylactic anticoagulation and antiplatelet therapy in patients with nephrotic syndrome remain controversial. However, in patients with idiopathic membranous nephropathy the benefits of anticoagulation may outweigh the risks.
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Treatment of Proteinuria
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Angiotensin-Converting Enzyme Inhibitors (ACEI) and Angiotensin II Receptor Blockers (ARB)
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These agents work by lowering intraglomerular capillary hydrostatic pressure and preventing the development of hemodynamically mediated focal segmental glomerulosclerosis. ARBs also decrease the formation of tumor growth factor (TGF)-β 1, which has been shown to play a role in progressive renal fibrosis.
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NSAIDs probably work by altering glomerular hemodynamics or glomerular basement membrane permeability, but their benefits must be balanced against the risk of inducing acute renal failure, salt and water retention, and hyperkalemia.
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A low-fat soy-protein diet that provides 0.7 g protein/kg/day has been demonstrated to be beneficial in decreasing urinary protein excretion and lipid profiles. However, protein-restricted diets in general may lead to malnutrition, which is a known potent predictor for death in end-stage renal disease (ESRD) patients.
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The prognosis in nephrotic syndrome is typically worse in patients with heavy proteinuria, renal insufficiency, and severe hypertension. The overall prognosis depends on etiology and is related to histology. For example, minimal change disease can have spontaneous remissions and is highly steroid responsive with an excellent prognosis. In contrast, spontaneous remission of primary focal segmental glomerulosclerosis (FSGS) is rare and the renal prognosis is relatively poor.