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Overview of Nephrotic Syndrome

By Navin Jaipaul, MD, MHS

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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 (primarily minimal change disease), mostly between ages 1½ and 4 yr. Congenital nephrotic syndromes appear during the first year of life. At younger ages (< 8 yr), 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 Manifestations) 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

Idiopathic

Fibrillary and immunotactoid GN

Focal segmental glomerulosclerosis

IgA nephropathy*

Membranoproliferative GN

Membranous nephropathy

Minimal change disease

Rapidly progressive GN*

Secondary causes

Metabolic

Amyloidosis

Diabetes mellitus

Immunologic

Cryoglobulinemia

Erythema multiforme

Immunoglobulin A–associated vasculitis*

Microscopic polyangiitis

Serum sickness

Sjögren syndrome

SLE*

Idiopathic

Castleman disease

Sarcoidosis

Neoplastic

Carcinoma (eg, bronchus, breast, colon, stomach, kidney)

Leukemia

Lymphomas

Melanoma

Multiple myeloma

Drug-related

Gold

Heroin

Interferon alfa

Lithium

NSAIDs

Mercury

Pamidronate

Penicillamine

Probenecid

Bacterial

Infective endocarditis

Leprosy

Syphilis

Protozoan

Filariasis

Helminthic infections

Loiasis

Malaria

Schistosomiasis (due to Schistosoma haematobium)

Toxoplasmosis

Viral

Epstein-Barr virus infection

Hepatitis B and C

Herpes zoster

HIV infection

Allergic

Antitoxins

Insect stings

Poison ivy or oak

Snake venoms

Genetic syndromes

Congenital nephrotic syndromes

  • Diffuse mesangial sclerosis

  • Finnish type, ie, nephrin defect

  • Corticosteroid-resistant nephrotic syndrome (podocin defect)

  • Denys-Drash syndrome

  • Familial FSGS

  • Nail-patella syndrome

Fabry disease

Familial FSGS

Hereditary nephritis*

Sickle cell disease

Physiologic

Adaptation to reduced nephrons

Morbid obesity

Oligomeganephronia

Miscellaneous

Chronic allograft nephropathy

Malignant hypertension

Preeclampsia

*More commonly manifests as nephritic syndrome.

Infectious and postinfectious causes.

FSGS = focal segmental glomerulonephritis;

GN =glomerulonephritis.

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 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

Edema (including ascites and pleural effusions)

Generalized capillary leak, due to hypoalbuminemia with decreased oncotic pressure

Possibly renal sodium retention

Infection (especially cellulitis and, in 2 to 6%, spontaneous bacterial peritonitis)

Unknown

Possibly loss of opsonins and immunoglobulins

Anemia

Loss of erythropoietin and transferrin

Changes in thyroid function test results (among patients previously hypothyroid, increased dose requirement for thyroid replacement hormone)

Loss of thyroid-binding globulin

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

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

Dyslipidemia

Increased hepatic lipoprotein synthesis

Coronary artery disease in adults

Dyslipidemia with atherosclerosis

Hypertension

Hypercoagulability

Hypertension in adults

Renal sodium retention

Bone disorder

Corticosteroid use

Chronic kidney disease

Unknown

Possibly hypovolemia, interstitial edema, and use of NSAIDs

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

  • Dyspnea (pleural effusion or laryngeal edema)

  • Arthralgia (hydrarthrosis)

  • 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: Complications of Nephrotic Syndrome).

Diagnosis

  • Urine random (spot) protein/creatinine ratio 3 or proteinuria 3 g/24 h

  • 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-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.

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.

  • BUN and creatinine concentrations vary by degree of renal impairment.

  • Serum albumin often is < 2.5 g/dL.

  • 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) 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)

  • Antinuclear antibodies

  • Hepatitis B and C serologic tests

  • Serum or urine protein electrophoresis

  • Cryoglobulins

  • Rheumatoid factor

  • Serologic test for syphilis (eg, rapid plasma reagin)

  • HIV antibody test

  • Complement levels (CH50, 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 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:

  • Infection

  • Hypertension

  • Significant azotemia

  • Hematuria

  • Thromboses in cerebral, pulmonary, peripheral, or renal veins

The recurrence rate is high in kidney transplantation patients with focal segmental glomerulosclerosis, IgA nephropathy, and membranoproliferative glomerulonephritis (especially type 2).

Treatment

  • Treatment of causative disorder

  • Angiotensin inhibition

  • Na restriction

  • Statins

  • Diuretics for excessive fluid overload

  • Rarely, nephrectomy

Treatment of disorder causing nephrotic syndrome

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.

Proteinuria treatment

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 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

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 is used as necessary.

Key Points

  • Nephrotic syndrome is most common in young children, usually idiopathic, and 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 h.

  • 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 and with angiotensin inhibition, Na restriction, and often diuretics and/or statins.

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Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • CUPRIMINE
  • AREDIA
  • LITHOBID
  • No US brand name

* This is the Professional Version. *