(See also Overview of Glomerular Disorders.)
Etiology
Nephrotic syndrome occurs at any age but is more prevalent in children (primarily minimal change disease), mostly between ages 1½ and 4 years. Congenital nephrotic syndromes appear during the first year of life. At younger ages (< 8 years), boys are affected more often than girls, but both are affected equally at older ages. Causes differ by age (see table Glomerular Disorders by Age and Presentation) and may be primary or secondary (see table 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.
Causes of Nephrotic Syndrome
Causes |
Examples |
Primary causes |
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Idiopathic |
Rapidly progressive GN* |
Secondary causes |
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Metabolic |
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Immunologic |
Cryoglobulinemia* |
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Idiopathic |
Castleman disease |
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Neoplastic |
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Drug-related |
Gold Heroin Interferon alfa Lithium NSAIDs Mercury Pamidronate Penicillamine Probenecid |
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Bacterial† |
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Protozoan† |
Schistosomiasis (due to Schistosoma haematobium) |
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Viral† |
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Allergic |
Antitoxins |
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Genetic syndromes |
Congenital nephrotic syndromes Hereditary nephritis* |
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Physiologic |
Adaptation to reduced nephrons Oligomeganephronia |
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Miscellaneous |
Chronic allograft nephropathy |
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* More commonly manifests as nephritic syndrome. |
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† Infectious and postinfectious causes. |
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FSGS = focal segmental glomerulonephritis; GN =glomerulonephritis; NSAID = nonsteroidal anti-inflammatory drug. |
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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 upregulate a circulating permeability factor or downregulate 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 of nephrotic syndrome
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 Complications of Nephrotic Syndrome); other physiologic factors also play a role.
Complications of Nephrotic Syndrome
Complication |
Contributing Factors |
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Edema (including ascites and pleural effusions) |
Generalized capillary leak, due to hypoalbuminemia with decreased oncotic pressure Possibly renal sodium retention |
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Infection (especially cellulitis and, in 2 to 6%, spontaneous bacterial peritonitis) |
Unknown Possibly loss of opsonins and immunoglobulins |
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Loss of erythropoietin and transferrin |
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Changes in thyroid function test results (among patients previously hypothyroid, increased dose requirement for thyroid replacement hormone) |
Loss of thyroid-binding globulin |
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Hypercoagulability and thromboembolism (especially renal vein thrombosis and pulmonary embolism, which occur in up to 5% of children and 40% of adults) |
Loss of antithrombin III Increased hepatic synthesis of clotting factors Platelet abnormalities Hyperviscosity caused by hypovolemia |
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Protein undernutrition in children (sometimes with brittle hair and nails, alopecia, and stunted growth) |
Loss of proteins Decreased hepatic production Sometimes decreased oral intake secondary to mesenteric edema |
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Increased hepatic lipoprotein synthesis |
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Coronary artery disease in adults |
Dyslipidemia with atherosclerosis Hypercoagulability |
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Hypertension in adults |
Renal sodium retention |
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Bone disorder |
Corticosteroid use Vitamin D deficiency due to loss of vitamin D binding protein |
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Unknown Possibly hypovolemia, interstitial edema, and use of nonsteroidal anti-inflammatory drugs (NSAIDs) |
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Proximal tubular dysfunction (acquired Fanconi syndrome), with glucosuria, aminoaciduria, potassium depletion, phosphaturia, renal tubular acidosis, bicarbonaturia, hypercitraturia, and uricosuria |
Toxic effects on proximal tubular cells secondary to large amounts of protein that they reabsorb |
Symptoms and Signs
Primary symptoms include anorexia, malaise, and frothy urine (caused by high concentrations of protein).
Fluid retention may cause
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Dyspnea (pleural effusion or laryngeal edema)
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Arthralgia (hydrarthrosis)
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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 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-hour measurement of urinary protein. The cause may be suggested by clinical findings (eg, systemic lupus erythematosus, 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-hour 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 body surface area (BSA) in a 24-hour collection (eg, values of 40 mg/dL protein and 10 mg/dL [884 micromol/L] creatinine in a random urine sample are equivalent to the finding of 4 g/1.73 m2 in a 24-hour 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-hour 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.
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 in nephrotic syndrome
Testing for secondary causes of nephrotic syndrome
The role of testing for secondary causes of nephrotic syndrome (see table 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:
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Serum glucose or glycosylated Hb (HbA1C)
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Antinuclear antibodies
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Serum and urine protein electrophoresis
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Cryoglobulins
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Rheumatoid factor
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Serologic test for syphilis (eg, rapid plasma reagin)
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Complement levels (C3, C4)
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 systemic lupus erythematosus, 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 years 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, immunoglobulin A (IgA) nephropathy, and membranoproliferative glomerulonephritis (especially type 2).
Treatment
Treatment of disorder causing nephrotic syndrome
Treatment of underlying disorders may include prompt treatment of infections (eg, staphylococcal endocarditis, malaria, syphilis, schistosomiasis), and stopping drugs (eg, gold, penicillamine, nonsteroidal anti-inflammatory drugs [NSAIDs]); these measures may cure nephrotic syndrome in specific instances.
Proteinuria treatment
Angiotensin inhibition (using angiotensin-converting enzyme [ACE] inhibitors or angiotensin II receptor blockers [ARBs]) 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 not recommended because of lack of demonstrated effect on progression.
Edema treatment
Sodium restriction (< 2 g sodium, 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 sodium restriction is ineffective or there is evidence of intravascular fluid overload. In severe cases, of nephrotic syndrome, IV albumin infusion followed by a loop diuretic may also be given to control edema.
Dyslipidemia treatment
Statins are indicated for dyslipidemia.
Limitation of saturated fat and cholesterol intake is recommended to help control dyslipidemia.
Hypercoagulability treatment
Management of infection risk
Nephrectomy for nephrotic syndrome
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.
Key Points
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Nephrotic syndrome is most common in young children, usually idiopathic, and most often minimal change disease.
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In adults, nephrotic syndrome is usually secondary, most often to diabetes or preeclampsia.
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Consider nephrotic syndrome in patients, particularly young children, with unexplained edema or ascites.
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Confirm nephrotic syndrome by finding spot protein/creatinine ratio ≥ 3 or urinary protein ≥ 3 g/24 hours.
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Do tests for secondary causes and renal biopsy selectively, based on clinical findings.
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Assume minimal change disease if a child with idiopathic nephrotic syndrome improves after treatment with corticosteroids.
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Treat the causative disorder with angiotensin inhibition, sodium restriction, and often diuretics and/or statins.
