Nephrotic syndrome is urinary excretion of > 3 g of protein/day due to a glomerular disorder plus edema and hypoalbuminemia. It is more common among children and has both primary and secondary causes. Diagnosis is by determination of urine protein/creatinine ratio in a random urine sample or measurement of urinary protein in a 24-h urine collection; cause is diagnosed based on history, physical examination, serologic testing, and renal biopsy. Prognosis and treatment vary by cause.
Etiology
Nephrotic syndrome occurs at any age but is more prevalent in children, mostly between ages 1½ and 4 yr. Congenital nephrotic syndromes appear during the first year of life (see Congenital Nephrotic Syndromes). At younger ages, boys are affected more often than girls, but both are affected equally at older ages. Causes differ by age (see Table 1: Glomerular Disorders by Age and Manifestations
) and may be primary or secondary (see Table 4: Causes of Nephrotic Syndrome).
) and may be primary or secondary (see Table 4: Causes of Nephrotic Syndrome).
The most common primary causes are the following:
Secondary causes account for < 10% of childhood cases but > 50% of adult cases, most commonly the following:
Amyloidosis, an underrecognized cause, is responsible for 4% of cases.
HIV-associated nephropathy is a type of focal segmental glomerulosclerosis that occurs in patients with AIDS (see HIV-Associated Nephropathy).
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Pathophysiology
Proteinuria occurs because of changes to capillary endothelial cells, the glomerular basement membrane (GBM), or podocytes, which normally filter serum protein selectively by size and charge.
The mechanism of damage to these structures is unknown in primary and secondary glomerular diseases, but evidence suggests that T cells may up-regulate a circulating permeability factor or down-regulate an inhibitor of permeability factor in response to unidentified immunogens and cytokines. Other possible factors include hereditary defects in proteins that are integral to the slit diaphragms of the glomeruli, activation of complement leading to damage of the glomerular epithelial cells and loss of the negatively charged groups attached to proteins of the GBM and glomerular epithelial cells.
Complications:
The disorder results in urinary loss of macromolecular proteins, primarily albumin but also opsonins, immunoglobulins, erythropoietin, transferrin, hormone-binding proteins (including thyroid-binding globulin and vitamin D-binding protein), and antithrombin III. Deficiency of these and other proteins contribute to a number of complications (see Table 5:Complications of Nephrotic Syndrome); other physiologic factors also play a role.
); other physiologic factors also play a role.
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Symptoms and Signs
Primary symptoms include anorexia, malaise, and frothy urine (caused by high concentrations of protein). Fluid retention may cause dyspnea (pleural effusion or laryngeal edema), arthralgia (hydrarthrosis), or abdominal pain (ascites or, in children, mesenteric edema).
Corresponding signs may develop, including peripheral edema and ascites. Edema may obscure signs of muscle wasting and cause parallel white lines in fingernail beds (Muehrcke lines).
Other symptoms and signs are attributable to the many complications of nephrotic syndrome (see Table 5: Complications of Nephrotic Syndrome).
).Diagnosis
Diagnosis is suspected in patients with edema and proteinuria on urinalysis and confirmed by random (spot) urine protein and creatinine levels or 24-h measurement of urinary protein. The cause may be suggested by clinical findings (eg, SLE, preeclampsia, cancer); when the cause is unclear, additional (eg, serologic) testing and renal biopsy are indicated.
Urine testing:
A finding of significant proteinuria (3 g protein in a 24-h urine collection) is diagnostic (normal excretion is < 150 mg/day). Alternatively, the protein/creatinine ratio in a random urine specimen usually reliably estimates grams of protein/1.73 m2 BSA in a 24-h collection (eg, values of 40 mg/dL protein and 10 mg/dL creatinine in a random urine sample are equivalent to the finding of 4 g/1.73 m2 in a 24-h specimen). Calculations based on random specimens may be less reliable when creatinine excretion is high (eg, during athletic training) or low (eg, in cachexia). However, calculations based on random specimens are usually preferred to 24-h collection because random collection is more convenient and less prone to error (eg, due to lack of adherence); more convenient testing facilitates monitoring changes that occur during treatment.
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Besides proteinuria, urinalysis may demonstrate casts (hyaline, granular, fatty, waxy,- or epithelial cell). Lipiduria, the presence of free lipid or lipid within tubular cells (oval fat bodies), within casts (fatty casts), or as free globules, suggests a glomerular disorder causing nephrotic syndrome. Urinary cholesterol can be detected with plain microscopy and demonstrates a Maltese cross pattern under crossed polarized light; Sudan staining must be used to show triglycerides.
Adjunctive testing:
Adjunctive testing helps characterize severity and complications.
It is not routinely necessary to measure levels of α- and γ-globulins, immunoglobulins, hormone-binding proteins, ceruloplasmin, transferrin, and complement components, but these levels may also be low.
Secondary causes:
The role of testing for secondary causes (see Table 4: Causes of Nephrotic Syndrome) is controversial because yield may be low. Tests are best done as indicated by clinical context. Tests may include the following:
) is controversial because yield may be low. Tests are best done as indicated by clinical context. Tests may include the following:
Test results may alter management and preclude the need for biopsy. For example, demonstration of cryoglobulins suggests mixed cryoglobulinemia (eg, from chronic inflammatory disorders such as SLE, Sjögren syndrome, or hepatitis C virus infection), and demonstration of a monoclonal protein on serum or urine protein electrophoresis suggests a monoclonal gammopathy (eg, multiple myeloma), especially in patients > 50 yr who have anemia.
Renal biopsy is indicated in adults to diagnose the disorder causing idiopathic nephrotic syndrome. Idiopathic nephrotic syndrome in children is most likely minimal change disease and is usually presumed without biopsy unless the patient fails to improve during a trial of corticosteroids. Specific biopsy findings are discussed under the individual disorders.
Prognosis
Prognosis varies by cause. Complete remissions may occur spontaneously or with treatment. The prognosis generally is favorable in corticosteroid-responsive disorders.
In all cases, prognosis may be worse in the presence of the following:
The recurrence rate is high in kidney transplantation patients with focal segmental glomerulosclerosis, IgA nephropathy, and membranoproliferative glomerulonephritis (especially type 2).
Treatment
Causative disorder:
Treatment of underlying disorders may include prompt treatment of infections (eg, staphylococcal endocarditis, malaria, syphilis, schistosomiasis), allergic desensitization (eg, for poison oak or ivy and insect antigen exposures), and stopping drugs (eg, gold, penicillamine
, NSAIDs); these measures may cure nephrotic syndrome in specific instances.
, NSAIDs); these measures may cure nephrotic syndrome in specific instances.
Proteinuria:
Angiotensin inhibition (using ACE inhibitors or angiotensin II receptor blockers) is indicated to reduce systemic and intraglomerular pressure and proteinuria. These drugs may cause or exacerbate hyperkalemia in patients with moderate to severe renal insufficiency.
Protein restriction is no longer recommended because of lack of demonstrated effect on progression.
Edema:
Na restriction (< 2 g Na, or about 100 mmol/day) is recommended for patients with symptomatic edema.
Loop diuretics are usually required to control edema but may worsen preexisting renal insufficiency and hypovolemia, hyperviscosity, and hypercoagulability and thus should be used only if Na restriction is ineffective or there is evidence of intravascular fluid overload.
Hyperlipidemia:
Statins are indicated for hyperlipidemia.
Limitation of saturated fat and cholesterol intake is recommended to help control hyperlipidemia.
Hypercoagulability:
Anticoagulants are indicated for treatment of thromboembolism, but few data exist to support their use as primary prevention.
Infection risk:
All patients should receive pneumococcal vaccination if not otherwise contraindicated.
Nephrectomy:
Rarely, bilateral nephrectomy is necessary in severe nephrotic syndrome because of persistent hypoalbuminemia. The same result can sometimes be achieved by embolizing the renal arteries with coils, thus avoiding surgery in high-risk patients. Dialysis is used as necessary.
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