(See also Overview of Glomerular Disorders Overview of Glomerular Disorders The hallmark of glomerular disorders is proteinuria, which is often in the nephrotic range (≥ 3 g/day). Glomerular disorders are classified based on urine changes as those that manifest predominantly... read more .)
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 Congenital Nephrotic Syndromes Congenital and infantile nephrotic syndromes are those that manifest during the first year of life. They include diffuse mesangial sclerosis and Finnish-type nephrotic syndrome. (See also Overview... read more 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 Glomerular Disorders by Age and Manifestations ) and may be primary or secondary (see table Causes of Nephrotic Syndrome 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 Amyloidosis Amyloidosis is any of a group of disparate conditions characterized by extracellular deposition of insoluble fibrils composed of misaggregated proteins. These proteins may accumulate locally... read more , an underrecognized cause, is responsible for 4% of cases.
HIV-associated nephropathy HIV-Associated Nephropathy HIV-associated nephropathy is characterized by clinical findings similar to those of focal segmental glomerulosclerosis and often biopsy features of collapsing glomerulopathy (a variant of focal... read more is a type of focal segmental glomerulosclerosis that occurs in patients with AIDS.
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 Complications of Nephrotic Syndrome ); other physiologic factors also play a role.
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)
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).
Urine random (spot) protein/creatinine ratio ≥ 3 or proteinuria ≥ 3 g/24 hours
Serologic testing and renal biopsy unless the cause is clinically obvious
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 Systemic Lupus Erythematosus (SLE) Systemic lupus erythematosus is a chronic, multisystem, inflammatory disorder of autoimmune etiology, occurring predominantly in young women. Common manifestations may include arthralgias and... read more , preeclampsia Preeclampsia and Eclampsia Preeclampsia is new-onset or worsening of existing hypertension with proteinuria after 20 weeks gestation. Eclampsia is unexplained generalized seizures in patients with preeclampsia. Diagnosis... read more , cancer Overview of Cancer Cancer is an unregulated proliferation of cells. Its prominent properties are A lack of differentiation of cells Local invasion of adjoining tissue Metastasis, which is spread to distant sites... read more ); when the cause is unclear, additional (eg, serologic) testing and renal biopsy are indicated.
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
Adjunctive testing helps characterize severity and complications.
Blood urea nitrogen (BUN) and creatinine concentrations vary by degree of renal impairment.
Serum albumin often is < 2.5 g/dL (25 g/L).
Total cholesterol and triglyceride levels are typically increased.
It is not routinely necessary to measure levels of alpha- and gamma-globulins, immunoglobulins, hormone-binding proteins, ceruloplasmin, transferrin, and complement components, but these levels may also be low.
Testing for secondary causes of nephrotic syndrome
The role of testing for secondary causes of nephrotic syndrome (see table Causes of Nephrotic Syndrome 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:
Serum glucose or glycosylated Hb (HbA1C)
Serum and urine protein electrophoresis
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 Systemic Lupus Erythematosus (SLE) Systemic lupus erythematosus is a chronic, multisystem, inflammatory disorder of autoimmune etiology, occurring predominantly in young women. Common manifestations may include arthralgias and... read more , Sjögren syndrome Sjögren Syndrome Sjögren syndrome is a relatively common chronic, autoimmune, systemic, inflammatory disorder of unknown cause. It is characterized by dryness of the mouth, eyes, and other mucous membranes due... read more , or hepatitis C virus Hepatitis C, Chronic Hepatitis C is a common cause of chronic hepatitis. It is often asymptomatic until manifestations of chronic liver disease occur. Diagnosis is confirmed by finding positive anti-HCV and positive... read more infection), and demonstration of a monoclonal protein on serum or urine protein electrophoresis suggests a monoclonal gammopathy (eg, multiple myeloma Multiple Myeloma Multiple myeloma is a cancer of plasma cells that produce monoclonal immunoglobulin and invade and destroy adjacent bone tissue. Common manifestations include lytic lesions in bones causing... read more ), especially in patients > 50 years who have anemia Overview of Decreased Erythropoiesis Anemia, a decrease in the number of red blood cells (RBCs), hemoglobin (Hb) content, or hematocrit (Hct), can result from decreased RBC production (erythropoiesis), increased RBC destruction... read more .
Renal biopsy Renal biopsy Biopsy of the urinary tract requires a trained specialist (nephrologist, urologist, or interventional radiologist). Indications for diagnostic biopsy include unexplained nephritic or nephrotic... read more is indicated in adults to diagnose the disorder causing idiopathic nephrotic syndrome. Idiopathic nephrotic syndrome in children is most likely minimal change disease Minimal Change Disease Minimal change disease causes abrupt onset of edema and heavy proteinuria, mostly in children. Renal function is typically normal. Diagnosis is based on clinical findings or renal biopsy. Prognosis... read more 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 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:
Thromboses in cerebral, pulmonary, peripheral, or renal veins
The recurrence rate is high in kidney transplantation patients Kidney Transplantation Kidney transplantation is the most common type of solid organ transplantation. (See also Overview of Transplantation.) The primary indication for kidney transplantation is End-stage renal failure... read more with focal segmental glomerulosclerosis Focal Segmental Glomerulosclerosis Focal segmental glomerulosclerosis is scattered (segmental) mesangial sclerosis that begins in some but not all (focal) glomeruli and eventually involves all glomeruli. It is most often idiopathic... read more , immunoglobulin A (IgA) nephropathy Immunoglobulin A Nephropathy Immunoglobulin A (IgA) nephropathy is deposition of IgA immune complexes in glomeruli, manifesting as slowly progressive hematuria, proteinuria, and, often, renal insufficiency. Diagnosis is... read more , and membranoproliferative glomerulonephritis Membranoproliferative Glomerulonephritis Membranoproliferative glomerulonephritis is a heterogeneous group of disorders that share mixed nephritic and nephrotic features and microscopic findings. They mostly affect children. Cause... read more (especially type 2).
Treatment of causative disorder
Diuretics for excessive fluid overload
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.
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 Hyperkalemia Hyperkalemia is a serum potassium concentration > 5.5 mEq/L (> 5.5 mmol/L), usually resulting from decreased renal potassium excretion or abnormal movement of potassium out of cells. There are... read more in patients with moderate to severe renal insufficiency.
Protein restriction is not recommended because of lack of demonstrated effect on progression.
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.
Statins are indicated for dyslipidemia Dyslipidemia Dyslipidemia is elevation of plasma cholesterol, triglycerides (TGs), or both, or a low high-density lipoprotein cholesterol level that contributes to the development of atherosclerosis... read more .
Limitation of saturated fat and cholesterol intake is recommended to help control dyslipidemia.
Anticoagulants are indicated for treatment of thromboembolism, but few data exist to support their use as primary prevention.
Management of infection risk
All patients should receive pneumococcal vaccination if not otherwise contraindicated.
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 Hemodialysis In hemodialysis, a patient’s blood is pumped into a dialyzer containing 2 fluid compartments configured as bundles of hollow fiber capillary tubes or as parallel, sandwiched sheets of semipermeable... read more is used as necessary.
Nephrotic syndrome is most common in young children, is usually idiopathic, and is most often minimal change disease.
In adults, nephrotic syndrome is usually secondary, most often to diabetes or preeclampsia.
Consider nephrotic syndrome in patients, particularly young children, with unexplained edema or ascites.
Confirm nephrotic syndrome by finding spot protein/creatinine ratio ≥ 3 or urinary protein ≥ 3 g/24 hours.
Do tests for secondary causes and renal biopsy selectively, based on clinical findings.
Assume minimal change disease if a child with idiopathic nephrotic syndrome improves after treatment with corticosteroids.
Treat the causative disorder with angiotensin inhibition, sodium restriction, and often diuretics and/or statins.
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