AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Nephrotic syndrome is not a disease. The term nephrotic syndrome was coined by Calvin and Goldberg. The syndrome is characterized by heavy proteinuria, hypoalbuminemia, edema, hypercholesterolemia, and normal renal function.

Because other eMedicine articles emphasize different glomerulopathies encountered in adults (eg, see Glomerulonephritis, Acute; Glomerulonephritis, Chronic; Glomerulonephritis, Crescentic; Glomerulonephritis, Diffuse Proliferative; Glomerulonephritis, Membranoproliferative; Glomerulonephritis, Membranous; Glomerulonephritis, Nonstreptococcal Associated with Infection; Glomerulonephritis, Poststreptococcal; or Glomerulonephritis, Rapidly Progressive), this article mainly focuses on pediatric nephrotic syndrome.

Classification

Nephrotic syndrome can be primary, occurring as part of a recognized systemic disease, or secondary, resulting from some evident cause.

Primary causes include the following:

• Postinfectious etiologies
• Collagen vascular disease (eg, systemic lupus erythematosus [SLE], rheumatoid arthritis, polyarteritis nodosa)
• Henoch-Schönlein purpura
• Hereditary nephritis
• Sickle cell disease
• Diabetes mellitus
• Amyloidosis
• Malignancy (eg, leukemia, lymphoma, Wilms tumor, pheochromocytoma)
• Toxins (eg, bee sting, poison ivy and oak, snake venom)
• Medications (eg, probenecid, fenoprofen, captopril, lithium, warfarin, penicillamine, mercury, gold, trimethadione, paramethadione)
• Heroin use

Secondary causes are related to postinfectious causes and include the following:

• Group A beta-hemolytic streptococci
• Syphilis
• Malaria
• Tuberculosis
• Viral infections (eg, varicella, hepatitis B, HIV type 1, infectious mononucleosis)

Nephrotic syndrome can be classified further according to histological findings. According to the International Study of Kidney Diseases in Childhood (ISKDC), 84.5% of all children have minimal-change nephrotic syndrome (MCNS), 9.5% have focal segmental glomerulosclerosis (FSGS), 2.5% have mesangial proliferation, and 3.5% have membranous nephropathy or other etiologies. Increasing trends of FSGS incidence in children with idiopathic nephrotic syndrome are being reported, but MCNS remains the most important cause of chronic renal disease in children. MCNS is a disorder of primary T lymphocyte dysfunction, where the lymphocytes are altered with IL2 expression during a relapse, resulting in increased vascular and glomerular basement membrane (GBM) permeability, leading to the typical clinical features seen in nephrotic syndrome.

The histological classifications of glomerular lesions associated with primary and secondary nephrotic syndrome are minimal-lesion nephrotic syndrome, diffuse mesangial hypercellularity, focal glomerulosclerosis, membranous glomerulonephritis, fibrillary glomerulosclerosis, and membranoproliferative glomerulonephritis.

The classifications of primary congenital nephrotic syndrome include infantile microcystic disease (Finnish type), infantile microcystic disease (non-Finnish type), diffuse mesangial sclerosis, minimal-lesion nephrotic syndrome, and FSGS.

The classifications of secondary congenital nephrotic syndrome include intrauterine infections (eg, toxoplasmosis, cytomegalovirus, rubella, syphilis), gonadal dysgenesis, nail-patella syndrome, and Lowe syndrome.

From a therapeutic perspective, nephrotic syndrome may be classified as steroid sensitive, steroid resistant, steroid dependent, or frequently relapsing.

Pathophysiology

Filtration of low molecular weight anionic plasma proteins across the glomerular basement membrane is normally prevented by a negatively charged filtration barrier, which consists of proteoglycan molecules of heparan sulfate. In persons with nephrotic syndrome, the concentration of heparan sulfate mucopolysaccharide in the basement membrane is lower, and large amounts of protein cross the barrier and are excreted.

High glomerular permeability leads to hyperalbuminuria and, eventually, to hypoalbuminemia. In turn, hypoalbuminemia lowers the plasma colloid osmotic pressure, causing greater transcapillary filtration of water and the development of edema.

Capillary hydrostatic pressure and the gradient of plasma to interstitial fluid oncotic pressure determine the movement of fluid from the vascular compartment to the interstitium. The oncotic pressure is mainly determined by the protein content, and the interstitial fluid has a protein concentration of 25-50% that of plasma. Fluid that is not absorbed back into the vascular system until it has reached the venous end of the capillary bed is usually absorbed by the lymphatics and returned back to the vascular space. In a steady state, the flux of water across the capillary wall can be expressed by the following formula:

Q_w = K ([P_c - P_i] - [p_p - [p_i]

In this formula, Q_w is net flux of water, K is the capillary filtration coefficient, P_c is plasma fluid hydrostatic pressure, and P_i is the interstitial fluid hydrostatic pressure. Also, p_p is the plasma oncotic pressure, and p_i is the interstitial fluid oncotic pressure. When the fall of Dp is wide, the amount of fluid filtered exceeds the maximal lymphatic flow, and edema occurs. In most patients with nephrotic syndrome, this causes a reduction in plasma volume. A hyperreninemic state ensues, resulting in increased sodium and water retention by the kidney.

An alternate hypothesis is that a condition of renal sodium retention occurs because of the proteinuria, but this is not related to intravascular volume or serum protein concentration. The evidence supporting this hypothesis is (1) sodium retention is observed even before the serum albumin level starts falling; (2) intravascular volume is normal or even increased in most patients with nephrotic syndrome; (3) Starling forces are unchanged in nephrotic syndrome until late in the disease course because p_i remains equivalent to p_p; and (4) the sites of renal sodium retention are predominantly in the distal nephron, not in the proximal nephron, as is expected by changes in Starling forces.

Hypoalbuminemia results mainly from increased catabolism and is not caused only by urinary loss of albumin; however, no evidence of decreased albumin synthesis exists in patients with nephrotic syndrome.

The structural changes believed to be responsible for causing proteinuria are (1) damage to the endothelial surface, causing loss of the negative charge; (2) damage to the glomerular basement membrane; and (3) effacement of the foot processes.

The foot processes are firmly attached to the visceral surface of the glomerular basement membrane. The space between the bases of the foot processes form the filtration slits, and this space constitutes the site for the convective forces that govern the filtration through the visceral epithelium. The podocyte forms a cover to the filtration slits. To date, they seem to have receptors for vasoactive agents such as endothelin, atrial natriureteric peptide, nitrous oxide, and, possibly, angiotensin II. Recently, congenital nephrotic syndrome of the Finnish type has been determined to be caused by mutations in the gene known as NPHS1. This gene codes for a cell adhesion protein called nephrin, which is synthesized by podocytes.

The role of nephrins in acquired kidney diseases in not known; however, nephrin and another podocyte protein called podocin are associated with the development of proteinuria, at least in the congenital type of nephrotic syndrome and in experimental models of glomerular disease.

Recently, the tandem endocytic receptors megalin and cubilin in the luminal membrane of proximal tubule cells have been shown to play an important role in endocytosis of albumin and low molecular weight proteins that may be filtered in the glomerulus. The presence of these receptors likely serves to protect the tubules from the toxic effects of undegraded albumin. These receptors are not specific for albumin. Therefore, proteinuria is now believed to be at least partly due to inhibition of albumin retrieval and degradation pathways.

Urinary immunoglobulin losses lower the patient's resistance to infections and increase the risk of serious sepsis and peritonitis. The loss of antithrombin III and plasminogen via urine and the simultaneous increase in clotting factors, especially factors I, VII, VIII, and X, increases the risk for arterial thrombosis, venous thrombosis, and pulmonary embolism, which occurs in 5% of children with nephrotic syndrome.

High glomerular permeability causes the excretion of vitamin D–binding protein and complexes in the urine, leading to (1) malabsorption of calcium and development of bone disease (eg, osteitis fibrosa cystica) because of enhanced parathyroid hormone production and (2) osteomalacia because of impairment in mineralization.

In the nephrotic state, levels of almost all serum lipids are elevated. Two pathogenic processes are operative, including (1) hypoproteinemia stimulating generalized protein synthesis in the liver, including the lipoproteins, and (2) diminution of lipid catabolism caused by reduced plasma levels of lipoprotein lipase.

Frequency

United States

The incidence of nephrotic syndrome is reportedly 2-7 cases in children per 100,000 children per year. However, in adults, the frequency varies significantly in different regions. Because of a much higher prevalence of diabetic nephropathy, which varies significantly from region to region, the incidence of nephrotic syndrome tends to be higher in the southern region compared to the northern region.

Mortality/Morbidity

• Although most adult patients have a glomerulopathy that is secondary to a systemic disease process (eg, diabetes mellitus, hypertension, SLE), primary or idiopathic glomerulonephritis is not uncommon.
• In most patients, the mortality rate is directly related to the primary disease process; however, once nephrotic syndrome manifests, the prognosis worsens because of (1) the increased incidence of renal failure and the complications secondary to nephrotic syndrome (eg, thrombotic episodes, hypoalbuminemia, hyperlipidemia) or (2) the treatment-related conditions (eg, increased incidence of infection from steroid therapy and blood dyscrasia from other immunosuppressive medications).

Race

• Because diabetes is now emerging as a major cause of nephrotic syndrome, American Indians, Hispanic persons, and African Americans have a clearly higher incidence of nephrotic syndrome compared to white persons.

Sex

• Incidence varies according to the type of glomerular disease.

Age

• Nephrotic syndrome is 15 times more common in children than in adults. Most cases of primary nephrotic syndrome are in children and are due to minimal-change disease. The age at onset varies with the type of nephrotic syndrome.
• In adults, the most common form of glomerulopathy causing nephrotic syndrome is membranous glomerulonephritis, followed by FSGS. In certain countries and in certain regions of the same country, diabetic nephropathy is emerging as a major cause of nephrotic syndrome.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• The first sign in children is usually swelling of the face; periorbital edema is a common presentation. This is followed by swelling of the entire body.
• Adults can present with edema of dependent parts. In most cases, this includes the ankles or legs.
• Facial swelling or anasarca can be the presenting symptom.
• In certain instances, patients notice frothy urine, which leads to investigations that reveal evidence of nephrotic syndrome.
• A hypercoagulable state leading to thrombotic complications, such as deep vein thrombosis of the calf veins or the renal vein, may be the first clue indicating nephrotic syndrome.

Physical

• Patients present with increasing edema over a few days or weeks, lethargy, poor appetite, weakness, and occasional abdominal pain.
• The initial episode and the subsequent relapses may follow an apparent viral upper respiratory tract infection.
• Edema is the predominant feature and initially develops around the eyes and lower extremities. With time, the edema becomes generalized and may be associated with an increase in weight, the development of an ascitic or pleural effusion, and a decline in urine output.
• Hematuria and hypertension are unusual but manifest in a minority of patients.

Causes

• Nephrotic syndrome reportedly has a familial cause in 2-8% of patients, and most familial cases involve siblings.
• Congenital nephrotic syndrome of the Finnish type is inherited in an autosomal recessive fashion. Recently, the gene responsible for this disease entity has been identified (ie, NPHS1).
• For the other causes, see Classification in Background.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Congestive heart failure

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Although the diagnosis is made based on clinical findings, results from the following investigations aid in determining the etiology and in planning and monitoring treatment.
• • Urine: In adults, perform a urinalysis, urine microscopy, testing for the ratio of urinary protein to urinary creatinine, and a determination of light-chain protein excretion.
  • • The normal amount of protein in the urine varies with age, but children excrete up to 4 mg/m²/h or 166 mg/1.73 m²/d. Adults excrete up to 150 mg/d.
    • Proteinuria may be measured by performing the urine dipstick test, an early morning urine (EMU) collection and determining the ratio of urinary protein to urinary creatinine, or a 24-hour quantitative urine protein excretion test.
    • A quantitative estimation of 24-hour urine protein excretion is the standard method, but EMU testing and determining the ratio of urinary protein to urinary creatinine is the method of choice for proteinuria quantification. Because this method is convenient for children who are incontinent, errors and difficulties associated with timed urine collection are avoided. This method also simplifies sample handling by the laboratory and is inexpensive. Nephrotic levels of proteinuria are associated with a ratio of urinary protein to urinary creatinine of greater than 2.
  • Blood: Perform a serum chemistry profile, including values for serum creatinine, urea nitrogen, serum albumin, and serum lipids. Also, perform a complete blood cell count, hepatitis B and hepatitis C testing, HIV screening, serum complement values, and varicella serology.
  • Other tests: In adult's, testing cryoglobulins and performing serum protein electrophoresis or urine protein electrophoresis can be useful for detecting the etiology of nephrotic syndrome.

Imaging Studies

• Renal ultrasonography is an essential tool to help establish the presence of 2 kidneys that are of normal size and architecture. The presence of hydronephrosis or cysts in the kidney that will undergo biopsy mandates caution. Similarly, small kidneys may not yield enough information and may be associated with an increased incidence of complications.

Other Tests

• If the clinical features are atypical, further tests, such as the following, may be useful:
• • Antistreptolysin O titers
  • Serum protein electrophoresis or immunofixation for light-chain proteins
  • Antinuclear antibodies

Procedures

• Renal biopsy: Before attempting a renal biopsy, ensure that a renal ultrasound scan is ordered to confirm that the patient has 2 functioning kidneys, that the kidneys are of normal size, and that the kidney architecture is normal (ie, devoid of cysts and vascular malformations). A renal biopsy is indicated in the following circumstances:
• • Congenital nephrotic syndrome
  • Children older than 8 years at onset
  • Steroid resistance
  • Frequent relapses or steroid dependency
  • Significant chronic nephritic manifestations
  • Adult nephrotic syndrome: Note that a renal biopsy is not indicated in adults when the nephrotic syndrome is due to an obvious cause such as diabetes mellitus, ie, when the patient has other diabetes-related overt complications.
• Abdominal fat pad biopsy or gingival biopsy
• • May be useful in adult patients to help diagnose either primary or secondary amyloidosis
  • Rarely performed in pediatric patients

Histologic Findings

The histologic findings are determined by the cause of the nephrotic syndrome. The details of the histologic findings are discussed in the appropriate articles. See Background for links to articles.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Acute management
• • With good parental and patient education and close outpatient follow-up care, hospitalization is not usually necessary. Hospitalization should be considered if a patient has generalized edema severe enough to cause respiratory distress, if a patient has tense scrotal or labial edema, if a patient is experiencing complications (eg, bacterial sepsis, peritonitis, pneumonia, thromboembolic phenomenon, failure to thrive), and if patient or family compliance with treatment is in doubt.
  • Diuretics and intravenous albumin may be needed. Furosemide (1 mg/kg/d) and spironolactone (2 mg/kg/d) are not always indicated but may help when fluid retention is severe, provided no signs of renal failure or volume contraction are evident. Achieving a satisfactory diuresis is difficult when the patient's serum albumin level is less than 1.5 g/dL. An effective regimen is to give salt-poor albumin at 1 g/kg, followed by intravenous furosemide. Close monitoring is obligatory to prevent pulmonary edema. Some evidence suggests that albumin may delay the response to steroids and may even induce more frequent relapses, probably by causing severe glomerular epithelial damage. The time required for remission is prolonged with a longer duration of administration and larger volumes of infused albumin. Fluid removal and weight loss remain transient unless proteinuria remits.
  • With regard to infection, oral penicillin can be prescribed as prophylaxis for children with gross edema. Abdominal paracentesis should be performed if the patient develops signs of peritonitis, and any bacterial infection should be treated promptly. A nonimmune patient with varicella should receive zoster immunoglobulin therapy if exposed to chickenpox, and acyclovir therapy should be administered if the patient develops chickenpox.
  • Among the nephropathies causing nephrotic syndrome, only minimal-change disease is treatable. Most patients with minimal-change disease are steroid-sensitive, especially children.

Diet

• The diet should provide adequate energy (caloric) intake and adequate protein (1-2 g/kg/d).
• A diet with no added salt is advised if the patient is edematous.
• Management of hyperlipidemia is controversial and could be of some importance if the nephrotic state is prolonged.
• Fluid restriction is not usually required unless the edema is severe.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Drugs used in the treatment of nephrotic syndrome include corticosteroids (eg, prednisone), levamisole, cyclophosphamide, and cyclosporine. The response to corticosteroids correlates with the histologic type of nephrotic syndrome. The ISKDC reports that 91.8% of patients who responded had minimal-change glomerulonephritis, compared with only 25% of patients who did not respond. In patients who do not respond to corticosteroid treatment and are younger than 6 years, approximately 50% had minimal-change glomerulonephritis; in those older than 6 years, only 3.6% had minimal-change glomerulonephritis.

The Southwest Pediatric Nephrology Study Group reports that 63% of patients with diffuse membranous hypercellularity and approximately 30% of patients with focal glomerular sclerosis responded to corticosteroid therapy. Congenital nephrotic syndrome is usually resistant to corticosteroid treatment.

Complications of corticosteroid treatment include obesity; cushingoid features; striae; retarded growth; and increased susceptibility to infections, hypertension, osteoporosis, cataracts, peptic ulcer disease, and diabetes mellitus.

A cornerstone of treatment of nephrotic syndrome in adults is ACE inhibitors and/or adrenergic receptor binders. The mechanism by which improvement is achieved is not clearly known. However, the reduction in proteinuria is not solely related to the decrement of intraglomerular pressure.

Previously, the traditional therapy for a decrement of proteinuria was the administration of nonsteroidal anti-inflammatory drugs (NSAIDs), which caused a significant decrease in glomerular filtration and thus reduced the proteinuria. However, this therapy is seldom used in current practice because the nephrotoxic effects of NSAIDs are enhanced in patients with nephrotic syndrome.

Drug Category: Corticosteroids

Have anti-inflammatory properties and modify the body's immune response to diverse stimuli.

Drug Category: Immunomodulators

These agents regulate key steps of the immune system.

Drug Name	Cyclophosphamide (Cytoxan)
Description	Antineoplastic drug chemically related to nitrogen mustard. Potent immunomodulator that has been used successfully in conditions that require immunosuppression. Highly effective for frequently relapsing steroid-sensitive nephrotic syndrome; half the children enter a prolonged remission. Researchers have formulated various protocols for different renal pathological lesions.
Adult Dose	40-50 mg/kg IV in 1 divided dose over 3 d; total dose may vary depending on nature and severity of condition
Pediatric Dose	3 mg/kg/d IV for 8 wk
Contraindications	Documented hypersensitivity, severely depressed bone marrow function
Interactions	Allopurinol may increase risk of bleeding or infection and may enhance myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones Chloramphenicol may increase half-life while decreasing metabolite concentrations; may increase effect of anticoagulants; coadministration with high doses of phenobarbital may increase rate of metabolism and leukopenic activity of cyclophosphamide; thiazide diuretics may prolong cyclophosphamide-induced leukopenia and neuromuscular blockade by inhibiting cholinesterase activity
Pregnancy	D - Unsafe in pregnancy
Precautions	Regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; regularly examine urine for RBCs, which may precede hemorrhagic cystitis

Drug Name	Cyclosporine (Sandimmune)
Description	Cyclic polypeptide that suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions (eg, delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, graft versus host disease) for a variety of organs. For children and adults, base dosing on ideal body weight.
Adult Dose	5-15 mg/kg PO qd or divided bid; IV dose is one third total oral dose via infusion over 6 h
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity; uncontrolled hypertension or malignancies; do not administer concomitantly with PUVA or UVB radiation in psoriasis because may increase risk of cancer
Interactions	Carbamazepine, phenytoin, isoniazid, rifampin, and phenobarbital may decrease concentrations; azithromycin, itraconazole, nicardipine, ketoconazole, fluconazole, erythromycin, verapamil, grapefruit juice, diltiazem, aminoglycosides, acyclovir, amphotericin B, and clarithromycin may increase toxicity; risk of acute renal failure, rhabdomyolysis, myositis, and myalgias increases when taken concurrently with lovastatin
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Evaluate renal and liver functions often by measuring BUN, serum creatinine, serum potassium, serum bilirubin, and liver enzyme levels; may increase risk of infection and lymphoma; reserve IV use only for those who cannot take PO

Drug Category: Immunosuppressants

Inhibit key steps that mediate immune reactions.

Drug Category: Diuretics

Used for symptomatic treatment of edema.

Drug Name	Spironolactone (Aldactone)
Description	For management of edema resulting from excessive aldosterone excretion. Competes with aldosterone for receptor sites in distal renal tubules, increasing water excretion while retaining potassium and hydrogen ions.
Adult Dose	25-200 mg/d PO qd or divided bid
Pediatric Dose	1.5-3.5 mg/kg/d PO divided q6-24h
Contraindications	Documented hypersensitivity; anuria, renal failure or hyperkalemia
Interactions	May decrease effect of anticoagulants; potassium and potassium-sparing diuretics may increase toxicity
Pregnancy	D - Unsafe in pregnancy
Precautions	Caution in renal and hepatic impairment

Drug Category: Antibiotics

Used for prophylaxis against bacterial infections.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• Long-term management
• • Immunization: Routine immunizations should be delayed until the patient is free of relapses and is off immunosuppression for 3 months. Pneumococcal and influenza vaccines are recommended but are not routinely used because their efficacy is not established. Children who have received immunosuppressive therapy in the preceding 3 months and are not immune to varicella should receive zoster immunoglobulin if they are exposed to chickenpox or shingles. These patients should also receive acyclovir if they develop chickenpox.
  • Treatment of relapses: Most patients experience relapses; recent data suggest rates of 76-97%, with frequently relapsing rates up to 50%. The first 2 relapses are treated in the same manner as the initial presentation; frequent relapses are treated with a maintenance dose of prednisone at 0.1-0.5 mg/kg on alternate days for 3-6 months and then tapered.
  • Monitoring steroid toxicity: Monitoring every 3 months in the outpatient clinic is necessary to help detect adverse effects and to record growth. A yearly checkup is necessary to help detect cataracts.

In/Out Patient Meds

• Other immunosuppressive medications: These medications are usually reserved for steroid-resistant cases in patients who are persistently edematous or steroid dependent with significant steroid-related adverse effects.
• • Levamisole is an immunostimulant with weak steroid-sparing effects and may permit the reduction, or even cessation, of prednisone therapy. The recommended dose is 2.5 mg/kg on alternating days for 4-12 months. Adverse effects are rare, but neutropenia and encephalopathy have been reported. This drug is not commonly used.
  • Cyclophosphamide at 3 mg/kg/d for 8 weeks is highly effective for patients who have frequently relapsing steroid-sensitive nephrotic syndrome, and half the children enter a prolonged remission. Associated complications include bone marrow suppression, hair loss, azoospermia, hemorrhagic cystitis, malignancy, mutations, and infertility.
  • Cyclosporin is an inhibitor of T-lymphocyte function and is indicated when relapses occur after cyclophosphamide treatment. Cyclosporin may be preferable in a pubertal male who is at risk of developing cyclophosphamide-induced azoospermia. Cyclosporin is highly effective maintenance therapy for patients with steroid-sensitive nephrotic syndrome who are able to stop steroids or take lower doses; however, some evidence suggests that remission is maintained as long as cyclosporin is administered but relapses are frequent when treatment is discontinued. Cyclosporin can be nephrotoxic and can cause hirsutism, hypertension, and gingival hypertrophy.

Complications

• Infection is the major complication; patients have an increased susceptibility to infection with Streptococcus pneumoniae, Haemophilus influenzae, Escherichia coli, and other gram-negative organisms. Varicella infection is also common. The most common infectious complications are bacterial sepsis, cellulitis, pneumonia, and peritonitis. Proposed explanations for these complications include decreased immunoglobulin levels, edema fluid acting as a culture medium, protein deficiency, decreased bactericidal activity of the leukocytes, immunosuppressive therapy, decreased perfusion of the spleen caused by hypovolemia, and urinary loss of a complement factor (properdin factor B) that opsonizes certain bacteria.
• Thromboembolism is dependent on the etiology of the nephrotic syndrome. It is encountered most frequently in patients with membranous glomerulonephritis, less frequently in patients with FSGS, and least frequently in patients with diabetic glomerulopathy.
• • The factors involved in the development of venous and arterial thromboembolism include thrombocytosis, enhanced platelet and red blood cell aggregation, and increased coagulability. Venous and arterial thrombus in a variety of sites has been described in the literature.
  • Not uncommonly, patients with nephrotic syndrome present with life-threatening thrombotic episodes such as pulmonary embolism, especially when the underlying glomerular lesion is membranous glomerulonephritis.
  • Renal vein thrombosis in children with childhood nephrotic syndrome is uncommon except in association with congenital nephrotic syndrome. Hoyer et al found pulmonary embolism in 28% of children with nephrotic syndrome. Subclinical episodes of thromboembolism may be more common in children with nephrotic syndrome than is presently appreciated.
• Hypovolemia occurs when hypoalbuminemia decreases the plasma oncotic pressure, resulting in a loss of plasma water into the interstitium and causing a decrease in circulating blood volume. Hypovolemia is generally observed only when the patient's serum albumin level is less than 1.5 g/dL. Symptoms include vomiting, abdominal pain, and diarrhea. The signs include cold hands and feet, delayed capillary filling, oliguria, and tachycardia. Hypotension is a late feature.
• Acute renal failure may indicate an underlying glomerulonephritis but is more often precipitated by hypovolemia or sepsis. Edema of the kidneys that causes a pressure-mediated reduction in the glomerular filtration rate has also been hypothesized.
• Hypertension may signify an acute nephritis or may be part of the hyperreninemic state of nephrotic syndrome induced by hypovolemia and reduced perfusion of the kidneys.
• Failure to thrive may develop in patients with chronic edema, including ascites and pleural effusion. Failure to thrive may be caused by anorexia, hypoproteinemia, increased protein catabolism, or frequent infectious complications. Edema of the gut may cause defective absorption, leading to chronic malnutrition.
• Tetany is a reported complication. The hypocalcemia may be significant enough to cause tetany. A positive Chvostek or Trousseau sign may be present.
• Adverse effects of treatment may occur. Corticosteroids and other immunosuppressive drugs (eg, cyclophosphamide, levamisole, cyclosporin) all have significant adverse effects.

Prognosis

• The prognosis for patients with primary nephrotic syndrome varies depending on the histological type.
• The prognosis is worse with congenital nephrotic syndrome, resulting in death from renal failure in 3-18 months in most cases.
• The prognosis for children with minimal-change glomerulonephritis is excellent.
• • Most children respond to steroid therapy; nevertheless, approximately 50% have 1-2 relapses within 5 years and approximately 20% continue to relapse 10 years after diagnosis. Only 30% of children never have a relapse after the initial episode. Approximately 3% of patients who initially responded to steroids become steroid resistant.
  • Progressive renal insufficiency occurs in fewer than 1% of patients, and most deaths among patients with minimal-change glomerulonephritis are from infections and nonrenal complications.
  • Frequent relapses are more common with young age of onset and in boys.
  • A linear relationship exists between the length of remission and risk of subsequent relapse.
  • Poor patient response to steroid therapy seems to be the finding most predictive of a poor outcome, but children who present with hematuria and hypertension are more likely to be steroid resistant and have a poorer prognosis than those who do not present with hematuria and hypertension.
• Only approximately 20% of patients with FSGS undergo remission of proteinuria; an additional 10% improve but remain proteinuric. Many patients experience frequent relapses, become steroid dependent, or become steroid resistant. End-stage renal disease develops in 25-30% of patients with FSGS by 5 years and in 30-40% by 10 years.
• Approximately 50% of patients with diffuse mesangial proliferation undergo complete remission of proteinuria during steroid therapy, an additional 20% have delayed remission, approximately 20% have continued proteinuria, and 6% progress to renal insufficiency.
• The outlook for patients with membranoproliferative glomerulonephropathy is commonly regarded as poor, and the benefits of treatment are not clear. In some comparative studies, no difference was evident in the outcome between treated and untreated patients; 30% of patients developed end-stage renal disease within 5 years of diagnosis.

Patient Education

• Nephrotic syndrome is a chronic illness characterized by relapses and remissions, which can extend throughout childhood. Educate parents about how to regularly monitor their child's urine and how to record the results in a diary. The diary can also be used to write down an agreed plan for the management of relapses. Information booklets should be made available to the family. Peer support and psychological counseling may be helpful for some families.
• For excellent patient education resources, visit eMedicine's Hepatitis Center and Liver, Gallbladder, and Pancreas Center. Also, see eMedicine's patient education articles Hepatitis B, Hepatitis C, and Cirrhosis.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Recurrence risk in transplanted kidneys: The types of nephrotic syndrome that may recur in a transplanted kidney include primary nephrotic syndrome with FSGS, immunoglobulin A nephropathy, membranoproliferative glomerulonephritis, rarely membranous glomerulonephritis, and secondary nephrotic syndrome caused by SLE.

Special Concerns

• Future developments: The advent of deflazacort, a glucocorticoid with a lower incidence of adverse effects, may allow better immunosuppression with fewer adverse effects. Newer immunosuppressive agents (eg, tacrolimus, mycophenolate mofetil) may prove valuable.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Alkjaersig N, Fletcher AP, Narayanan M, Robson AM. Course and resolution of the coagulopathy in nephrotic children. Kidney Int. Mar 1987;31(3):772-80. [Medline].
• Arneil GC, Lam CN. Long-term assessment of steroid treatment of idiopathic childhood nephrosis. Am Heart J. Oct 1967;74(4):584-6. [Medline].
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Article Last Updated: Feb 1, 2007