eMedicine Specialties > Nephrology > Glomerular Diseases

Nephrotic Syndrome

Eric P Cohen, MD, Professor of Medicine, Nephrology Fellowship Program Director, Department of Medicine, Division of Nephrology, Medical College of Wisconsin; Nephrology Section Chief, Zablocki Veterans Affairs Hospital

Updated: Aug 25, 2009

Introduction

Background

Schematic drawing of the glomerular barrier. Podo = podocytes; GBM = glomerular basement membrane; Endo = fenestrated endothelial cells; ESL = endothelial cell surface layer (often referred to as the glycocalyx). Primary urine is formed through the filtration of plasma fluid across the glomerular barrier (arrows); in humans, the glomerular filtration rate (GFR) is 125 mL/min. The plasma flow rate (Q_p) is close to 700 mL/min, with the filtration fraction being 20%. The concentration of albumin in serum is 40 g/L, while the estimated concentration of albumin in primary urine is 4 mg/L, or 0.1% of its concentration in plasma. Reproduced from Haraldsson et al, Physiol Rev 88: 451-487, 2008, and by permission of the American Physiological Society (www.the-aps.org).

Nephrotic syndrome can be primary, being a disease specific to the kidneys, or it can be secondary, being a renal manifestation of a systemic general illness. In all cases, injury to glomeruli is an essential feature.

Primary causes of nephrotic syndrome include, in approximate order of frequency:

• Minimal-change nephropathy

• Focal glomerulosclerosis

• Membranous nephropathy

• Hereditary nephropathies

Secondary causes include, again in order of approximate frequency:

• Diabetes mellitus
• Lupus erythematosus
• Amyloidosis and paraproteinemias
• Viral infections (eg, hepatitis B, hepatitis C, human immunodeficiency virus [HIV] )
• Preeclampsia

Nephrotic-range proteinuria may occur in other kidney diseases, such as IgA nephropathy. In that common glomerular disease, one third of subjects may have nephrotic-range proteinuria.¹ Nephrotic syndrome may occur in persons with sickle cell disease and evolve to renal failure. Membranous nephropathy may complicate bone marrow transplantation, in association with graft versus host disease. Kidney diseases that affect tubules and interstitium, such as interstitial nephritis, will not cause nephrotic syndrome.

The above causes of nephrotic syndrome are largely those for adults, and this article will concentrate primarily on adult nephrotic syndrome.

However, nephrotic syndrome in infancy and childhood is an important entity. A study from New Zealand found the incidence of nephrotic syndrome to be almost 20 cases per million children under age 15 years.² In specific populations, such as those of Finnish or Mennonite origin, congenital nephrotic syndrome may occur in 1 in 10,000 or 1 in 500 births, respectively.³ According to the International Study of Kidney Diseases in Childhood (ISKDC), 84.5% of all children with primary nephrotic syndrome 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 another cause of the disease.^4,5 Increasing trends of FSGS incidence are being reported, but MCNS remains the most important cause of chronic renal disease in children.

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

Pathophysiology

Glomerular permeability

In a healthy individual, less than 0.1% of plasma albumin may traverse the glomerular filtration barrier.⁶ Controversy exists regarding the sieving of albumin across the glomerular permeability barrier. Specifically, it is proposed that there is ongoing albumin passage into the urine, in many grams per day, with equivalent substantial tubular uptake of albumin, the result being that the urine has 80 mg per day or less of daily albumin.⁷ This controversy is based on studies in experimental animals. However, studies of humans with tubular transport defects suggest that the glomerular urinary space albumin concentration is 3.5 mg/L.⁸ With this concentration, and a normal daily glomerular filtration rate (GFR) of 150 liters, one would expect no more than 525 mg per day of albumin in the final urine. Amounts above that level point to glomerular disease.

The glomerular capillaries are lined by a fenestrated endothelium that sits on the glomerular basement membrane, which in turn is covered by glomerular epithelium, or podocytes, which envelops the capillaries with cellular extensions called foot processes. In between the foot processes are the filtration slits. These 3 structures — the fenestrated endothelium, glomerular basement membrane, and glomerular epithelium — are the glomerular filtration barrier. (See Image 1.)

Filtration of plasma water and solutes is extracellular and occurs through the endothelial fenestrae and filtration slits. The importance of the podocytes and the filtration slits is shown by genetic diseases. Thus, in congenital nephrotic syndrome of the Finnish type, the gene for nephrin, a protein of the filtration slit, is mutated, leading to nephrotic syndrome in infancy . Similarly, podocin, a protein of the podocytes, may be abnormal in a number of children with steroid-resistant focal glomerulosclerosis.

The glomerular structural changes that may cause proteinuria are (1) damage to the endothelial surface, (2) damage to the glomerular basement membrane, and/or (3) damage of the podocytes. One or more of these mechanisms may be seen in any one type of nephrotic syndrome. Albuminuria alone may occur, or, with greater injury, leakage of all plasma proteins, (ie, proteinuria) may take place.

Proteinuria that is more than 85% albumin is selective proteinuria. Albumin has a net negative charge, and it is proposed that loss of glomerular membrane negative charges could be important in causing albuminuria. Nonselective proteinuria, being a glomerular leakage of all plasma proteins, would not involve changes in glomerular net charge but rather a generalized defect in permeability. This construct does not permit clear-cut separation of causes of proteinuria, except in minimal-change nephropathy, in which proteinuria is selective.

Pathogenesis of edema

An increase in glomerular permeability leads to albuminuria and eventually to hypoalbuminemia. In turn, hypoalbuminemia lowers the plasma colloid osmotic pressure, causing greater transcapillary filtration of water throughout the body and thus 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. 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 capillary hydrostatic pressure, and P_i is the interstitial fluid hydrostatic pressure, while p_p is the plasma oncotic pressure, and p_i is the interstitial fluid oncotic pressure. With a high enough capillary hydrostatic pressure or a low enough intravascular oncotic pressure, the amount of fluid filtered exceeds the maximal lymphatic flow, and edema occurs. In patients with nephrotic syndrome, this causes a reduction in plasma volume, with a secondary increase of sodium and water retention by the kidneys.

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 to serum protein concentration. The evidence supporting this hypothesis includes the fact that (1) sodium retention is observed even before the serum albumin level starts falling and (2) intravascular volume is normal or even increased in most patients with nephrotic syndrome. This could occur if intraluminal protein directly stimulated renal epithelial sodium reabsorption.⁹

A third possible mechanism is an enhanced peripheral capillary permeability to albumin, as shown by radioisotopic technique in human studies of 60 patients with nephrotic syndrome.¹⁰ This would then lead to increased tissue oncotic pressure and fluid retention in the peripheral tissues.

Metabolic consequences of proteinuria

In the nephrotic syndrome, levels of serum lipids are usually elevated. This can occur via (1) hypoproteinemia that stimulates protein, including lipoprotein, synthesis by the liver, and (2) diminution of lipid catabolism caused by reduced plasma levels of lipoprotein lipase.

The loss of antithrombin III and plasminogen via urine, along with the simultaneous increase in clotting factors, especially factors I, VII, VIII, and X, increases the risk for venous thrombosis and pulmonary embolism. In the first 6 months that a patient has nephrotic syndrome, the occurrence rate of venous thrombosis may reach 10%.¹¹

Vitamin D – binding protein may be lost in the urine, leading to hypovitaminosis D, with malabsorption of calcium and development of bone disease.¹²

Urinary immunoglobulin losses may lower the patient's resistance to infections and increase the risk of sepsis and peritonitis.

Frequency

United States

Incidence of important causes of nephrotic syndrome, in number per million population. The left panel shows systemic causes, and the right panel lists primary renal diseases that can cause nephrotic syndrome. fgs = focal glomerulosclerosis, MN = membranous nephropathy, min change = minimal-change nephropathy. Data are in part from Swaminathan et al and Bergesio et al.

International

Biopsy studies in children with nephrotic syndrome have shown similar types of histology in India and Turkey, compared with what one would expect in Western countries.^13,14 In Pakistani adults with nephrotic syndrome, the spectrum of histologies of kidney biopsies has been found to be similar to that seen in western countries.¹⁵

Glomerular disease may be associated with schistosomal infection, as could occur in Egypt.¹⁶

So-called "tropical nephrotic syndrome" may not be a true entity. Doe et al summarized the evidence for causes of nephrotic syndrome in African children.¹⁷ All of the typical histologies may be found on kidney biopsy. The connection of nephrotic syndrome to quartan malaria is not well-established. Indeed, Pakasa and Sumaili call attention to the apparent decline of parasite-associated nephrotic syndrome in the Congo.^18,19 It is possible that the perceived association between nephrotic syndrome and parasitic infections was coincidental, as supported by the ongoing and probably increasing occurrence of chronic kidney disease in the Congo.¹⁹

Mortality/Morbidity

• In the preantibiotic era, infection was a major factor in the mortality rate among patients with nephrotic syndrome.²⁰ Treatments for nephrotic syndrome and its complications appear to have reduced the morbidity and mortality once associated with the syndrome.
• A study by Donadio et al of 140 patients with idiopathic membranous nephropathy, 89 of whom received no treatment with corticosteroids or immunosuppressive drugs and 51 of whom were treated primarily with short-term courses of prednisone alone, found that the patients' survival rates were  the same as those expected for the general population.²¹ This supports the clinical practice of expectant management for the first 6 months, without immunosuppression, in persons with membranous nephropathy and a low risk for progression.²²
• The prognosis may worsen because of (1) an increased incidence of renal failure and the complications secondary to nephrotic syndrome, including thrombotic episodes and infection, or (2) treatment-related conditions, such as infectious complications of immunosuppressive treatments.
• In secondary nephrotic syndromes, morbidity and mortality are related to the primary disease process, such as diabetes or lupus, although in diabetic nephropathy, the magnitude of proteinuria itself relates directly to mortality.²³

Race

• Because diabetes is major cause of nephrotic syndrome, American Indians, Hispanics, and African Americans have a higher incidence of nephrotic syndrome than do white persons.
• HIV nephropathy is a complication of HIV that is unusual in whites; it is seen with greater frequency in African Americans.²⁴
• Focal glomerulosclerosis appears to be overrepresented in African American children, as compared with white children, as a cause of nephrotic syndrome.²⁵

Sex

• There is a male predominance in the occurrence of nephrotic syndrome, as there is for chronic kidney disease in general. This male overrepresentation is also seen in paraneoplastic membranous nephropathy.²⁶
• However, lupus nephritis affects mostly women.

Age

A schema of the average patient ages associated with various common forms of the nephrotic syndrome.

Clinical

History

• The first sign of nephrotic syndrome in children is usually swelling of the face; this is followed by swelling of the entire body.
• Adults can present with dependent edema.
• Foamy urine may be a presenting feature.
• A thrombotic complication, such as deep vein thrombosis of the calf veins or even a pulmonary embolus, may be the first clue indicating nephrotic syndrome.
• Additional historical features that appear can be related to the cause of nephrotic syndrome. Thus, the recent start of a nonsteroidal anti-inflammatory drug (NSAID) or a 10-year history of diabetes may be very relevant.

Physical

• Edema is the predominant feature of nephrotic syndrome and initially develops around the eyes and legs. With time, the edema becomes generalized and may be associated with an increase in weight, the development of ascites, or pleural effusions.
• Hematuria and hypertension manifest in a minority of patients.
• Additional features on exam will vary according to cause and as a result of whether or not renal function impairment exists. Thus, in the case of longstanding diabetes, there may be diabetic retinopathy, which correlates closely with diabetic nephropathy. If the kidney function is reduced, there may be hypertension and/or anemia.

Causes

• The usual causes of nephrotic syndrome are discussed above (see Background). They include primary kidney diseases, such as minimal-change nephropathy, membranous nephropathy, and focal glomerulosclerosis, as well as systemic diseases, such as diabetes mellitus, lupus erythematosus, and amyloidosis.
• Congenital and hereditary focal glomerulosclerosis may result from mutations of genes that code for podocyte proteins, including nephrin, podocin, or the cation channel 6 protein.
• Nephrotic syndrome can result from drugs of abuse, such as heroin.
• Nephrotic-range proteinuria occurring in the third trimester of pregnancy is the classical finding of preeclampsia. In that condition, also known as toxemia, there is hypertension as well. It may occur de novo or it may be superimposed on another chronic kidney disease. In the latter case, there will have been preexisting proteinuria that will have worsened during pregnancy.
• Medication can cause nephrotic syndrome. This includes the very infrequent occurrence of minimal-change nephropathy with NSAID use, and the occurrence of membranous nephropathy with the administration of gold and penicillamine, which are older drugs used for rheumatic diseases; there have also been reports of focal glomerulosclerosis in association with bisphosphonates. Although recognized, these associations have not yet been quantified.
• Nephrotic-range proteinuria could occur with the use of anticancer agents, such as bevacizumab, that inhibit vascular endothelial growth factor (VEGF).²⁷ However, the clinical picture of this complication is of a thrombotic microangiopathy rather than of nephrotic syndrome per se.
• The association of membranous nephropathy with cancer is a clinical dilemma. This association presumably results from immune complex injury to the glomerulus caused by cancer antigens.
  
  While there are about 6000 new cases of membranous nephropathy per year in the United States, there are 1.5 million new cases of nonskin cancer. Therefore, from the oncologist’s standpoint, the problem of paraneoplastic membranous nephropathy is trivial. Nonetheless, a carefully performed analysis from France suggested that the cancer rate in persons with membranous nephropathy is approximately 10-fold higher than it is in the general population, especially in individuals over age 65 years.²⁶ In that study, 50% of membranous nephropathy cases were diagnosed before the diagnosis of cancer. Thus, in some subjects with membranous nephropathy, one should consider the possibility of an undiagnosed cancer.

Differential Diagnoses

Other Problems to Be Considered

Heart failure may cause a similar presentation to that of nephrotic syndrome. In typical cases of heart failure, however, there will be a history of heart disease and/or features of poor heart function on exam, such as a third heart sound and even low blood pressure. In heart failure without kidney disease, there will be little or no proteinuria. Nephrotic syndrome with renal impairment, such as may occur in IgA nephropathy, may cause secondary reduction in heart function, with cardiomegaly on exam. Such cases would typically be hypertensive and there will be substantial proteinuria on urinalysis. 

Subjects with cirrhosis may have substantial fluid retention, both as ascites and as peripheral edema. Unless there is associated kidney disease, however, there will be little or no proteinuria in cirrhosis.

Workup

Laboratory Studies

• Urinalysis is the first test used in the diagnosis of nephrotic syndrome.
  • Nephrotic range proteinuria will be apparent by 3+ or 4+ readings on the dipstick, or by semiquantitative testing by sulfosalicylic acid. A 3+ reading is 300 mg/dL of urinary protein or more, which is 3 g/L or more and thus in the nephrotic range. The chemistry of the dipsticks is such that albumin is the major protein that is tested.
  • Glucosuria points to diabetes.
  • The urine sediment exam may show cells and/or casts.
  • Waxy casts mark proteinuric renal disease. By use of a polarizing microscope, one can see oval fat bodies and also fatty casts. These point to the nephrotic syndrome. They occur because of glomerular filtration of lipoproteins, the uptake of these by the tubular cells that then fall off into the urine. Viewed by polarizer, the oval fat bodies and fatty casts cause a "Maltese cross" appearance.
  • The presence of more than 2 red blood cells (RBCs) per high power field is indicative of microhematuria. Microhematuria may occur in membranous nephropathy but not in minimal-change nephropathy. Glomerular disease may allow RBCs to traverse the damaged glomerular basement membrane, and the RBCs in the sediment may then be deformed, or dysmorphic. This points to glomerular disease with inflammation and destruction of the normal structures, ie, a nephritis (and thus a nephritic picture). This could occur in, for example, nephrotic syndromes associated with IgA nephropathy or proliferative glomerulonephritis.
  • More than 2 granular casts in the entire sediment is a biomarker for renal parenchymal disease. Variable-caliber granular casts point to reduced renal function.
• Urinary protein is measured by a timed collection or a single, spot collection.²⁸ A timed collection is typically done over a 24-hour period, starting at 7 am and finishing the next day at the same time. In healthy individuals, there are no more than 150 mg of total protein in a 24-hour urine collection. A single, spot urine collection is much easier to obtain. When the ratio of urine protein to urine creatinine is greater than 2 g/g, this corresponds to 3 grams of urine protein per day or more.
• The exact type of urine protein is of potential interest. This can be tested by urine protein electrophoresis. Proteinuria that does not include albumin may point to overflow proteinuria that occurs in paraproteinemias, such as multiple myeloma. There has been intermittent interest in establishing whether proteinuria is "selective" for albumin, being more than 85% composed of albumin, as opposed to nonselective. In the case of selective proteinuria, there could be a charge-selective leak of albumin across the glomerular barrier, perhaps due to reduced negative charges on that barrier, whereas nonselective proteinurias would point to more substantial glomerular injury and perhaps also to lesser response to prednisone treatment.
• Serum tests for kidney function are essential. Serum creatinine will be in the normal range in uncomplicated nephrotic syndrome, such as that occurring in minimal-change nephropathy. In children, the serum creatinine level will be lower than it is in adults. The normal adult serum creatinine level is approximately 1 mg/dL, whereas that of a child aged 5 years will be about 0.5 mg/dL. Values higher than this indicate reduced kidney function.  
• The serum albumin is classically low in nephrotic syndrome, being below its normal range of 3.5-4.5 g/dL. A single-center study showed that when a patient's serum albumin level was normal, rather than low, focal glomerulosclerosis, rather than other conditions, tended to be the cause of nephrotic syndrome.²⁹

Imaging Studies

• Ultrasonographic scanning can be used to determine whether a patient possesses 2 kidneys and to demonstrate their echogenicity. Individuals with a single kidney may be prone to developing focal glomerulosclerosis. Having only 1 kidney is also a relative contraindication to kidney biopsy. Increased renal echogenicity by ultrasonography is consistent with intrarenal fibrosis, ie, chronic disease with reduced kidney function.

Other Tests

• In infants with nephrotic syndrome, genetic testing for the NPHS1 and NPHS2 mutations may be useful. These are mutations of nephrin and podocin, respectively. In children with steroid-resistant nephrotic syndrome, testing for the NPHS2 mutation may be indicated.
• In adults with nephrotic syndrome, tests for hepatitis B and C, HIV, and even syphilis may be useful. Tests for lupus, including ANA, anti-dsDNA, and complement, may be useful. Testing for antineutrophil cytoplasmic antibodies (ANCA) is not indicated in typical nephrotic syndrome, because that test is associated with rapidly progressive glomerulonephritis, which presents with a nephritic picture rather than one that is typically nephrotic. Tests for previous streptococcal infection, such as antistreptolysin O, are not usually indicated for nephrotic syndrome, since postinfectious glomerulonephritis usually causes a nephritic picture, not nephrotic syndrome.
• Future studies for urinary biomarkers by which the cause and severity of nephrotic syndrome may be identified may become available.³⁰

Procedures

• For childhood nephrotic syndrome, a renal biopsy is indicated for the following:
  • Congenital nephrotic syndrome
  • Children older than 8 years at onset
  • Steroid resistance
  • Frequent relapses or steroid dependency
  • Significant nephritic manifestations
• Adult nephrotic syndrome of unknown origin may require a renal biopsy for diagnosis.
• A renal biopsy is not indicated in adults when nephrotic syndrome is due to an obvious cause, such as diabetes mellitus. Thus, a subject with diabetes, diabetic retinopathy, and the nephrotic syndrome may well have diabetic nephropathy and not need to undergo kidney biopsy.
• Abdominal fat-pad biopsy or gingival biopsy
  • May be useful in adult patients to help diagnose either primary or secondary amyloidosis

Histologic Findings

Histologic findings in nephrotic syndrome are determined by the disease's cause. It is worth noting that in clinical experience, glomerular disease has been found to cause of nephrotic-range proteinuria, not tubular disease. This appears to contradict the proposal that tubular function determines proteinuria.⁷

Staging

There are histopathologic stages for membranous nephropathy but not for other causes of nephrotic syndrome.

Treatment

Medical Care

Acute management of childhood nephrotic syndrome

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 he or she has complications (eg, bacterial sepsis, peritonitis, pneumonia, thromboembolism, failure to thrive), or if patient or family compliance with treatment is in doubt.

Diuretics will be needed; furosemide (1 mg/kg/d) and spironolactone (2 mg/kg/d) will 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. Albumin at 1 g/kg may be given, followed by intravenous furosemide. Complications may occur, including 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. 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 should be given if the patient develops chickenpox.

Acute management of adult nephrotic syndrome

The principles for acute management of adults with nephrotic syndrome are similar to those for children. Diuretics will be needed; furosemide, spironolactone, and even metolazone may be used. Volume depletion may occur with diuretic use, which should be monitored by assessment of symptoms, weight, pulse, and blood pressure.

Anticoagulation has been advocated by some for use in preventing thromboembolic complications, but its use in primary prevention is of unproven value.

Hypolipidemic agents may be used, but if the nephrotic syndrome cannot be controlled, there will be persistent hyperlipidemia.

In secondary nephrotic syndrome, such as that associated with diabetic nephropathy, angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin II receptor blockers are widely used. These may reduce proteinuria by reducing the systemic blood pressure, by reducing intraglomerular pressure, and also by direct action on podocytes.

Specific treatment

Specific treatment of nephrotic syndrome depends on the disease's cause. Thus, glucocorticosteroids, such as prednisone, are used for minimal-change nephropathy. Prednisone and cyclophosphamide are useful in some forms of lupus nephritis. Secondary amyloidosis with nephrotic syndrome may respond to anti-inflammatory treatment of the primary disease.

Surgical Care

Surgery is not applicable in itself for the treatment of nephrotic syndrome. It is possible that patients with nephrotic syndrome may have poor wound healing, which places emphasis on optimal medical treatments.

Consultations

Depending on the cause of nephrotic syndrome, a patient may need specialty consultation. For example, an individual with lupus nephritis may benefit from rheumatologic consultation.

Diet

• For patients with nephrotic syndrome, their diet should provide adequate energy (caloric) intake and adequate protein (1-2 g/kg/d). Supplemental dietary protein is of no proven value.
• A diet with no added salt will help to limit fluid overload.
• Management of hyperlipidemia could be of some importance if the nephrotic state is prolonged.
• Fluid restriction per se is not required.

Activity

There are no activity restrictions for patients with nephrotic syndrome. Ongoing activity, rather than bedrest, will reduce the risk of blood clots.

Medication

Drugs used in the remittive treatment of nephrotic syndrome include corticosteroids (prednisone), cyclophosphamide, and cyclosporine, while drugs used to reduce edema include diuretics and those administered to reduce the proteinuria include ACE inhibitors and angiotensin II receptor blockers.

Corticosteroids

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

Prednisone (Sterapred)

Immunosuppressant for treatment of autoimmune disorders. May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. May be administered as a single dose in the morning or as divided doses. Studies show that a single dose is equally effective and greatly improves compliance.

Dosing

Adult

60 mg/m²/d PO, titrate to a maximum 80 mg/m²/d until remission; then, 40 mg/m²/d, titrate to 60 mg/m² qod for 4 wk

Pediatric

1 to 2 mg/kg/d; taper over 2 wk as symptoms resolve

Interactions

Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics

Contraindications

Documented hypersensitivity, viral infection, peptic ulcer disease, hepatic dysfunction, connective tissue infections, fungal or tubercular infections, GI disease

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use; blood pressure may increase and should be treated; sudden stopping may cause adrenal crisis, ie, hypoadrenalism

Immunomodulators

These agents regulate key steps of the immune system.

Cyclophosphamide (Cytoxan)

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 of the children enter a prolonged remission.
Doses (below) are based on published studies. This drug is used for the time required to induce remission and should be continued thereafter, but probably not for more than a year.

Dosing

Adult

1-2 mg/kg/d PO; continue for 3-6 mo beyond remission

Pediatric

2 mg/kg/d PO

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

Contraindications

Documented hypersensitivity, severely depressed bone marrow function

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; regularly examine urine for RBCs, which may precede hemorrhagic cystitis

Cyclosporine (Sandimmune, Neoral, Gengraf)

Cyclic polypeptide that suppresses cell-mediated immune reactions.
For children and adults, base dosing on ideal body weight.

Dosing

Adult

Up to 3 mg/kg PO in divided doses

Pediatric

Administer as in adults

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

Contraindications

Documented hypersensitivity; uncontrolled hypertension or malignancies; do not administer concomitantly with PUVA or UVB radiation in psoriasis because may increase risk of cancer

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

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

Immunosuppressants

Inhibit key steps that mediate immune reactions.

Mycophenolate (CellCept, Myfortic)

Inhibits inosine monophosphate dehydrogenase and suppresses de novo purine synthesis by lymphocytes, thereby inhibiting their proliferation. Inhibits antibody production.

Dosing

Adult

Mycophenolate mofetil (CellCept): 500 to 1500 mg PO bid
Mycophenolate sodium (Myfortic): 360 to 720 mg PO bid

Pediatric

CellCept oral suspension: 600 mg/m² PO bid; 1 g PO bid maximum

Interactions

May elevate levels of acyclovir and ganciclovir; antacids and cholestyramine decrease absorption, reducing levels (do not administer together); probenecid may increase levels of mycophenolate; salicylates may increase toxicity of mycophenolate

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

May cause nausea, vomiting, and diarrhea; may experience less gastrointestinal side effects with Myfortic preparation

Diuretics

Used for symptomatic treatment of edema.

Furosemide (Lasix)

Increases urine output by inhibiting sodium transport in ascending loop of Henle and distal renal tubule. Dose must be individualized to patient. Depending on response, administer at increments of 20-40 mg, no sooner than 6-8 h after the previous dose, until desired diuresis occurs.

Dosing

Adult

20-80 mg/d PO/IV; titrate up to 200 mg/d for severe edema

Pediatric

1-2 mg/kg/dose PO; not to exceed 6 mg/kg/dose; do not administer >q6h
When treating infants, titrate in increments of 1 mg/kg/dose until satisfactory effect achieved
1 mg/kg IV/IM slowly under close supervision; not to exceed 6 mg/kg

Interactions

Metformin decreases concentrations; interferes with hypoglycemic effect of antidiabetic agents and antagonizes muscle-relaxing effect of tubocurarine; auditory toxicity appears to be increased with coadministration with aminoglycosides; hearing loss of varying degrees may occur; anticoagulant activity of warfarin may be enhanced when taken concurrently; increased plasma lithium levels and toxicity are possible when taken concurrently

Contraindications

Documented hypersensitivity; hepatic coma, anuria, state of severe electrolyte depletion

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Perform frequent serum electrolyte, glucose, creatinine, uric acid, calcium, and BUN determinations during first few months of therapy and periodically thereafter

Spironolactone (Aldactone)

For management of edema resulting from excessive aldosterone excretion. Competes with aldosterone for receptor sites in distal renal tubules, thus enhancing sodium excretion.

Dosing

Adult

25-200 mg/d PO qd or divided bid

Pediatric

1.5-3.5 mg/kg/d PO divided q6-24h

Interactions

May decrease effect of anticoagulants; simultaneous use of potassium, potassium-sparing diuretics, or ACE inhibitors may cause hyperkalemia.

Contraindications

Documented hypersensitivity; anuria, renal failure or hyperkalemia

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in renal and hepatic impairment

Angiotensin-converting Enzyme (ACE) Inhibitors

These agents improve hypertension by inhibiting renin or angiotensin II production.

Lisinopril (Prinivil, Zestril)

Inhibitor of the enzyme that converts angiotensin I to angiotensin II.

Dosing

Adult

2.5 mg PO qd, increasing to 20 mg/d, as required

Pediatric

Not established

Interactions

NSAIDs may reduce hypotensive effects of lisinopril; ACE inhibitors may increase digoxin, lithium, and allopurinol levels; rifampin decreases lisinopril levels; probenecid may increase lisinopril levels; the hypotensive effects of ACE inhibitors may be enhanced when given concurrently with diuretics; may cause hyperkalemia when used together with potassium-sparing diuretics such as spironolactone, or when used together with potassium supplements

Contraindications

Documented hypersensitivity to drug and related products

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Pregnancy category D in second and third trimesters of pregnancy, causes fetal malformations if used during a late-term pregnancy; may cause elevations in the serum creatinine related to hemodynamic change, or even renal failure when used in a subject with renal artery stenosis; caution in severe congestive heart failure; may cause cough in up to 5% of subjects on this drug or other drugs in its class

Angiotensin II Receptor Antagonist

These agents inhibit angiotensin II activity by interfering with the binding of formed angiotensin II to its endogenous receptor.

Losartan (Cozaar)

Angiotensin II receptor antagonist that blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II. May induce a more complete inhibition of the renin-angiotensin system than ACE inhibitors, does not affect the response to bradykinin, and is less likely to be associated with cough and angioedema. For patients unable to tolerate ACE inhibitors.

Dosing

Adult

25-100 mg PO qd or divided bid

Pediatric

Not established

Interactions

May increase digoxin, lithium, and allopurinol levels; probenecid may increase losartan levels; coadministration with diuretics increases hypotensive effects of losartan; NSAIDs may reduce hypotensive effects of losartan; may increase risk of hyperkalemia if taken concurrently with potassium supplements or other potassium-sparing diuretics

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Pregnancy category D in second and third trimesters of pregnancy, caution in patients with unilateral or bilateral renal artery stenosis

Follow-up

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 of steroid-responsive nephrotic syndromes - Most patients experience relapses; data suggest relapse rates of 76-97%, with frequently relapsing rates of 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, with the drug then tapered.
  • Monitoring steroid toxicity - Monitoring every 3 months in the outpatient clinic is necessary to help detect adverse effects and to record growth. Supplemental calcium and vitamin D may attenuate bone loss. A yearly checkup is necessary to help detect cataracts.
• Ongoing use and adjustment of diuretics and angiotensin antagonists are necessary according to the amount of edema and proteinuria that a patient has. This requires periodic monitoring.

Inpatient & Outpatient Medications

• Other immunosuppressive medications - These medications are usually reserved for steroid-resistant cases in patients who are persistently edematous or for steroid-dependent patients with significant steroid-related adverse effects.
  • Cyclophosphamide may benefit patients who have frequently relapsing steroid-sensitive nephrotic syndrome. Associated complications include bone marrow suppression, hair loss, azoospermia, hemorrhagic cystitis, malignancy, mutations, and infertility.
  • Cyclosporine is indicated when relapses occur after cyclophosphamide treatment. Cyclosporine may be preferable in a pubertal male who is at risk of developing cyclophosphamide-induced azoospermia. Cyclosporine is a 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 although remission is maintained as long as cyclosporine is administered, relapses are frequent when treatment is discontinued. Cyclosporine can be nephrotoxic and can cause hirsutism, hypertension, and gingival hypertrophy.

Deterrence/Prevention

Amniocentesis may show high levels of alpha-fetoprotein when the fetus has congenital nephrotic syndrome of the Finnish type.³¹ This may assist in management and counseling.

Complications

• Infection is a major concern in nephrotic syndrome; 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.
• The occurrence of hyperlipidemia may be considered a typical feature of the nephrotic syndrome, rather than a mere complication. It is related to the hypoproteinemia and low serum oncotic pressure of nephrotic syndrome, which then leads to reactive hepatic protein synthesis, including of lipoproteins.³² Some of the elevated serum lipoproteins are filtered at the glomerulus, leading to lipiduria and the classical findings of oval fat bodies and fatty casts in the urine sediment.
• Atherosclerotic vascular disease appears to occur in greater frequency in subjects with nephrotic syndrome than in healthy subjects of the same age. Curry and Roberts showed that the frequency and extent of coronary artery disease stenoses were greater in patients with nephrotic syndrome than in nonnephrotic control subjects.³³ When their study was published (1977), lipid-lowering treatments were less widely used than they are today. Accordingly, the average highest serum total cholesterol in this series was over 400 mg/dL. That is in the range of serum cholesterol seen in familial hypercholesterolemia, a disease that predisposes individuals to myocardial infarction.
• Hypocalcemia is common in the nephrotic syndrome, but rather than being a true hypocalcemia, it is usually caused by a low serum albumin level. Nonetheless, low bone density and abnormal bone histology are reported in association with nephrotic syndrome. This could be caused by urinary losses of vitamin D – binding proteins, with consequent hypovitaminosis D and, as a result, reduced intestinal calcium absorption. Tessitore et al reported that when the GFR was normal, subjects with the nephrotic syndrome had no consistent calcium or bony abnormalities.³⁴ Yet in that same study, when the GFR was reduced, there were bone mineralization defects found by biopsy.
  
  A later study found osteomalacia on bone biopsy in over half of adults who had longstanding nephrotic syndrome but whose GFR was preserved.¹² A further complication derives from therapies, especially prednisone use. Low bone mass may be found, in relation to cumulative steroid dose.³⁵ This subject remains controversial; as reported by Leonard et al, in 2004, intermittent corticosteroid treatment of childhood steroid-sensitive nephrotic syndrome does not appear to be associated with bone mineral deficits.³⁶ It is possible that long duration of either the nephrotic syndrome or treatments for it are the important risk factors for bone disease in these subjects.
• Venous thrombosis and pulmonary embolism are well-known complications of the nephrotic syndrome. Hypercoagulability in these subjects appears to derive from urinary loss of anticoagulant proteins, such as anti-thrombin III, compounded by elevations in procoagulant proteins, such as fibrinogen.
  
  A study by Mahmoodi et al of almost 300 patients with nephrotic syndrome confirmed that venous thromboembolism (VTE) was almost 10 times higher in these persons than in the normal population.¹¹ In the normal population, the average per year incidence of VTE is 0.1-0.2%, whereas among the patients in Mahmoodi's study, the incidence rate reached 1%. Moreover, that risk appeared especially elevated during the first 6 months of nephrotic syndrome, being at almost 10%. This high incidence may justify the routine use of preventive anticoagulation treatment during the first 6 months of a persistent nephrotic syndrome.
  
  Mahmoodi's study also showed an increased risk of arterial thrombotic events, including coronary and cerebrovascular ones, in nephrotic syndrome. Unlike the risk of VTE, which was related to proteinuria, this arterial risk was related to usual risk factors for arterial disease, such as hypertension, diabetes, smoking, and reduced GFR.
• 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 GFR has also been hypothesized.
• Hypertension related to fluid retention and reduced kidney function may occur.
• 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.
• Adverse treatment effects may occur. Corticosteroids and other immunosuppressive drugs have significant adverse effects.

Prognosis

• The prognosis for patients with primary nephrotic syndrome depends on its cause.
• The prognosis with congenital nephrotic syndrome is bad. Survival beyond several months is possible only with dialysis and kidney transplantation.
• Only approximately 20% of patients with focal glomerulosclerosis 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% of these patients by 10 years.
• The prognosis for children with minimal-change nephropathy is very good.
  • Most children respond to steroid therapy; still, about 50% of children have 1 or 2 relapses within 5 years and approximately 20% of them 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 respond to steroids become steroid-resistant.
  • Poor patient response to steroid therapy may predict a poor outcome, and children who present with hematuria and hypertension are more likely to be steroid-resistant and have a poorer prognosis than are those who do not present with these conditions.
  • In adult nephrotic syndrome, there is a similar variability according to the underlying cause.
  • In adult minimal-change nephropathy, there is a burden of relapse similar to that of children. However, the long-term prognosis for kidney function in patients with this disease is excellent, with little risk of renal failure.
  • As noted, the prognosis of membranous nephropathy is good in terms of patient survival, being the same as that of the unaffected population.
  • In diabetic nephropathy with nephrotic syndrome, there is usually a good response to angiotensin blockade, with reduction of proteinuria to low, sub-nephrotic levels. However, true remission is uncommon. Cardiovascular morbidity and mortality increase as kidney function declines, and some subjects will eventually need dialysis or a kidney transplant.
  • In primary amyloidosis, prognosis is not good, even with intensive chemotherapy. In secondary amyloidosis, remission of the underlying cause, such as rheumatoid arthritis, is followed by remission of the amyloidosis and its associated nephrotic syndrome.

Patient Education

• Childhood nephrotic syndrome
  • Nephrotic syndrome is a chronic illness characterized by relapses and remissions, which can extend throughout childhood. There will be illness from the disease and from its treatment. Parents may monitor their child's urine and record the results in a diary. The diary can also be used to write down an agreed-upon plan for the management of relapses. Information booklets should be given to the family. Peer support and psychological counseling may be helpful for some families.
  • Progression to renal failure will require preparation for dialysis and/or kidney transplantation.
• Adult nephrotic syndrome
  • Forms of nephrotic syndrome that cannot be cured may evolve into renal failure and the need for dialysis or kidney transplantation.

Miscellaneous

Medicolegal Pitfalls

• A study using the Cochrane database has put into question whether prednisone treatment is beneficial in adult minimal-change nephropathy.³⁷ Nonetheless, when the nephrotic syndrome causes illness, by uncomfortable edema or associated coagulopathy, treatment would appear needed.
• The role of preventive anticoagulation in nephrotic syndrome has been reported, but there is no proof that it is beneficial.
• Hyperlipidemia occurs in nephrotic syndrome, and it can be controlled with lipid-lowering agents. Older studies have reported a predisposition to atherosclerosis in patients with nephrotic syndrome, but there is no evidence-based proof that lipid-lowering drugs improve renal or patient outcomes.

Special Concerns

• A better understanding of the mechanisms of nephrotic syndrome may greatly change the management of the disease. For example, confirmation of the role of galactose in some forms of focal glomerulosclerosis may lead to novel and better treatments.³⁸

Multimedia

Media file 1: Schematic drawing of the glomerular barrier. Podo = podocytes; GBM = glomerular basement membrane; Endo = fenestrated endothelial cells; ESL = endothelial cell surface layer (often referred to as the glycocalyx). Primary urine is formed through the filtration of plasma fluid across the glomerular barrier (arrows); in humans, the glomerular filtration rate (GFR) is 125 mL/min. The plasma flow rate (Q_p) is close to 700 mL/min, with the filtration fraction being 20%. The concentration of albumin in serum is 40 g/L, while the estimated concentration of albumin in primary urine is 4 mg/L, or 0.1% of its concentration in plasma. Reproduced from Haraldsson et al, Physiol Rev 88: 451-487, 2008, and by permission of the American Physiological Society (www.the-aps.org).

Media file 2: Incidence of important causes of nephrotic syndrome, in number per million population. The left panel shows systemic causes, and the right panel lists primary renal diseases that can cause nephrotic syndrome. fgs = focal glomerulosclerosis, MN = membranous nephropathy, min change = minimal-change nephropathy. Data are in part from Swaminathan et al and Bergesio et al.

Media file 3: A schema of the average patient ages associated with various common forms of the nephrotic syndrome.

References

1. Neelakantappa K, Gallo GR, Baldwin DS. Proteinuria in IgA nephropathy. Kidney Int. Mar 1988;33(3):716-21. [Medline].

2. Wong W. Idiopathic nephrotic syndrome in New Zealand children, demographic, clinical features, initial management and outcome after twelve-month follow-up: results of a three-year national surveillance study. J Paediatr Child Health. May 2007;43(5):337-41. [Medline].

3. Niaudet P. Genetic forms of nephrotic syndrome. Pediatr Nephrol. Dec 2004;19(12):1313-8. [Medline].

4. International Study of Kidney Disease in Children. Primary nephrotic syndrome in children: clinical significance of histopathologic variants of minimal change and of diffuse mesangial hypercellularity. A Report of the International Study of Kidney Disease in Children. Kidney Int. Dec 1981;20(6):765-71. [Medline].

5. International Study of Kidney Disease in Children. The primary nephrotic syndrome in children. Identification of patients with minimal change nephrotic syndrome from initial response to prednisone. J Pediatr. Apr 1981;98(4):561-4. [Medline].

6. Haraldsson B, Nyström J, Deen WM. Properties of the glomerular barrier and mechanisms of proteinuria. Physiol Rev. Apr 2008;88(2):451-87. [Medline].

7. Russo LM, Bakris GL, Comper WD. Renal handling of albumin: a critical review of basic concepts and perspective. Am J Kidney Dis. May 2002;39(5):899-919. [Medline].

8. Norden AG, Lapsley M, Lee PJ, Pusey CD, Scheinman SJ, Tam FW. Glomerular protein sieving and implications for renal failure in Fanconi syndrome. Kidney Int. Nov 2001;60(5):1885-92. [Medline].

9. Hamm LL, Batuman V. Edema in the nephrotic syndrome: new aspect of an old enigma. J Am Soc Nephrol. Dec 2003;14(12):3288-9. [Medline].

10. Rostoker G, Behar A, Lagrue G. Vascular hyperpermeability in nephrotic edema. Nephron. Jul 2000;85(3):194-200. [Medline].

11. Mahmoodi BK, ten Kate MK, Waanders F, Veeger NJ, Brouwer JL, Vogt L. High absolute risks and predictors of venous and arterial thromboembolic events in patients with nephrotic syndrome: results from a large retrospective cohort study. Circulation. Jan 15 2008;117(2):224-30. [Medline].

12. Mittal SK, Dash SC, Tiwari SC, Agarwal SK, Saxena S, Fishbane S. Bone histology in patients with nephrotic syndrome and normal renal function. Kidney Int. May 1999;55(5):1912-9. [Medline].

13. Kumar J, Gulati S, Sharma AP, Sharma RK, Gupta RK. Histopathological spectrum of childhood nephrotic syndrome in Indian children. Pediatr Nephrol. Jul 2003;18(7):657-60. [Medline].

14. Ozkaya N, Cakar N, Ekim M, Kara N, Akkök N, Yalçinkaya F. Primary nephrotic syndrome during childhood in Turkey. Pediatr Int. Aug 2004;46(4):436-8. [Medline].

15. Kazi JI, Mubarak M. Pattern of glomerulonephritides in adult nephrotic patients--report from SIUT. J Pak Med Assoc. Nov 2007;57(11):574. [Medline].

16. Barsoum R. The changing face of schistosomal glomerulopathy. Kidney Int. 2004;66:2472-2484.

17. Doe JY, Funk M, Mengel M, et al. Nephrotic syndrome in African children: lack of evidence for 'tropical nephrotic syndrome'?. Nephrol Dial Transplant. 2006;21:672-676.

18. Pakasa NM, Sumaili EK. The nephrotic syndrome in the Democratic Republic of Congo. N Engl J Med. Mar 9 2006;354(10):1085-6. [Medline].

19. Sumaili EK, Krzesinski JM, Zinga CV, Cohen EP, Delanaye P, Munyanga SM, et al. Prevalence of chronic kidney disease in Kinshasa: results of a pilot study from the Democratic Republic of Congo. Nephrol Dial Transplant. Jan 2009;24(1):117-22. [Medline].

20. Arneil GC, Lam CN. Long-term assessment of steroid therapy in childhood nephrosis. Lancet. Oct 15 1966;2(7468):819-21. [Medline].

21. Donadio JV Jr, Torres VE, Velosa JA, Wagoner RD, Holley KE, Okamura M. Idiopathic membranous nephropathy: the natural history of untreated patients. Kidney Int. Mar 1988;33(3):708-15. [Medline].

22. du Buf-Vereijken PW, Branten AJ, Wetzels JF. Idiopathic membranous nephropathy: outline and rationale of a treatment strategy. Am J Kidney Dis. Dec 2005;46(6):1012-29. [Medline].

23. Jude EB, Anderson SG, Cruickshank JK, et al. Natural history and prognostic factors of diabetic nephropathy in type 2 diabetes. Quart J Med. 2002;95:371-7. [Medline].

24. Kopp JB, Winkler C. HIV-associated nephropathy in African Americans. Kidney Int Suppl. Feb 2003;S43-9. [Medline].

25. Bonilla-Felix M, Parra C, Dajani T, Ferris M, Swinford RD, Portman RJ. Changing patterns in the histopathology of idiopathic nephrotic syndrome in children. Kidney Int. May 1999;55(5):1885-90. [Medline].

26. Lefaucheur C, Stengel B, Nochy D, et al. Membranous nephropathy and cancer: Epidemiologic evidence and determinants of high-risk cancer association. Kidney Int. Oct 2006;70(8):1510-7. [Medline].

27. George BA, Zhou XJ, Toto R. Nephrotic syndrome after bevacizumab: case report and literature review. Am J Kidney Dis. Feb 2007;49(2):e23-9. [Medline].

28. Cohen EP, Lemann J. The role of the laboratory in evaluation of kidney function. Clin Chem. 1991;37:785-796.

29. Gupta K, Iskandar SS, Daeihagh P, et al. Distribution of pathologic findings in individuals with nephrotic proteinuria according to serum albumin. Nephrol Dial Transplant. May 2008;23(5):1595-9. [Medline].

30. Varghese SA, Powell TB, Budisavljevic MN, et al. Urine biomarkers predict the cause of glomerular disease. J Am Soc Nephrol. 2007;18:913-22. [Medline].

31. Rapola J. Congenital nephrotic syndrome. Pediatr Nephrol. Jul 1987;1(3):441-6. [Medline].

32. Appel GB, Blum CB, Chien S, Kunis CL, Appel AS. The hyperlipidemia of the nephrotic syndrome. Relation to plasma albumin concentration, oncotic pressure, and viscosity. N Engl J Med. Jun 13 1985;312(24):1544-8. [Medline].

33. Curry RC Jr, Roberts WC. Status of the coronary arteries in the nephrotic syndrome. Analysis of 20 necropsy patients aged 15 to 35 years to determine if coronary atherosclerosis is accelerated. Am J Med. Aug 1977;63(2):183-92. [Medline].

34. Tessitore N, Bonucci E, D'Angelo A, Lund B, Corgnati A, Lund B, et al. Bone histology and calcium metabolism in patients with nephrotic syndrome and normal or reduced renal function. Nephron. 1984;37(3):153-9. [Medline].

35. Gulati S, Godbole M, Singh U, Gulati K, Srivastava A. Are children with idiopathic nephrotic syndrome at risk for metabolic bone disease?. Am J Kidney Dis. Jun 2003;41(6):1163-9. [Medline].

36. Leonard MB, Feldman HI, Shults J, Zemel BS, Foster BJ, Stallings VA. Long-term, high-dose glucocorticoids and bone mineral content in childhood glucocorticoid-sensitive nephrotic syndrome. N Engl J Med. Aug 26 2004;351(9):868-75. [Medline].

37. Palmer SC, Nand K, Strippoli GF. Interventions for minimal change disease in adults with nephrotic syndrome. Cochrane Database Syst Rev. Jan 23 2008;CD001537. [Medline].

38. Savin VJ, McCarthy ET, Sharma R, Charba D, Sharma M. Galactose binds to focal segmental glomerulosclerosis permeability factor and inhibits its activity. Transl Res. Jun 2008;151(6):288-92. [Medline].

39. 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].

40. Bergesio F, Ciciani AM, Santostefano M, et al. Renal involvement in systemic amyloidosis-an Italian retrospective study on epidemiological and clinical data at diagnosis. Nephrol Dial Transplant. 2007;22:1608-1618. [Medline].

41. Brukamp K, Doyle AM, Bloom RD, Bunin N, Tomaszewski JE, Cizman B. Nephrotic syndrome after hematopoietic cell transplantation: do glomerular lesions represent renal graft-versus-host disease?. Clin J Am Soc Nephrol. Jul 2006;1(4):685-94. [Medline].

42. Cattran DC, Alexopoulos E, Heering P, Hoyer PF, Johnston A, Meyrier A, et al. Cyclosporin in idiopathic glomerular disease associated with the nephrotic syndrome : workshop recommendations. Kidney Int. Dec 2007;72(12):1429-47. [Medline].

43. Chesney RW, Novello AC. Forms of nephrotic syndrome more likely to progress to renal impairment. Pediatr Clin North Am. Jun 1987;34(3):609-27. [Medline].

44. Deen WM. What determines glomerular capillary permeability?. J Clin Invest. Nov 2004;114(10):1412-4. [Medline].

45. Eddy AA, Symons JM. Nephrotic syndrome in childhood. Lancet. Aug 23 2003;362(9384):629-39. [Medline].

46. Filler G, Young E, Geier P. Is there really an increase in non-minimal change nephrotic syndrome in children?. Am J Kidney Dis. Dec 2003;42(6):1107-13.

47. Fliser D, Zurbruggen, Mutschler E, et al. Coadministration of albumin and furosemide in patients with the nephrotic syndrome. Kidney Int. 1999;55:629-634. [Medline].

48. Gorensek MJ, Lebel MH, Nelson JD. Peritonitis in children with nephrotic syndrome. Pediatrics. Jun 1988;81(6):849-56. [Medline].

49. Grundy SM, Vega GL. Rationale and management of hyperlipidemia of the nephrotic syndrome. Am J Med. Nov 1989;87(5N):3N-11N. [Medline].

50. Haws RM, Baum M. Efficacy of albumin and diuretic therapy in children with nephrotic syndrome. Pediatrics. Jun 1993;91(6):1142-6. [Medline].

51. Hodson EM, Craig JC, Willis NS. Evidence-based management of steroid-sensitive nephrotic syndrome. Pediatr Nephrol. Nov 2005;20(11):1523-30. [Medline].

52. Hoyer PF, Gonda S, Barthels M, et al. Thromboembolic complications in children with nephrotic syndrome. Risk and incidence. Acta Paediatr Scand. Sep 1986;75(5):804-10. [Medline].

53. Ingulli E, Tejani A. Racial differences in the incidence and renal outcome of idiopathic focal segmental glomerulosclerosis in children. Pediatr Nephrol. Jul 1991;5(4):393-7. [Medline].

54. Keane WF, St Peter JV, Kasiske BL. Is the aggressive management of hyperlipidemia in nephrotic syndrome mandatory?. Kidney Int (suppl). 1992;38:s134-s141. [Medline].

55. Koskimies O, Vilska J, Rapola J, Hallman N. Long-term outcome of primary nephrotic syndrome. Arch Dis Child. Jul 1982;57(7):544-8. [Medline].

56. Lewis MA, Baildom EM, Davis N, et al. Nephrotic syndrome: from toddlers to twenties. Lancet. Feb 4 1989;1(8632):255-9. [Medline].

57. Mendoza SA, Tune BM. Management of the difficult nephrotic patient. Pediatr Clin North Am. Dec 1995;42(6):1459-68. [Medline].

58. Mongeau JG, Corneille L, Robitaille P, et al. Primary nephrosis in childhood associated with focal glomerular sclerosis: is long-term prognosis that severe?. Kidney Int. Dec 1981;20(6):743-6. [Medline].

59. Niaudet P, Broyer M, Habib R. Treatment of idiopathic nephrotic syndrome with cyclosporin A in children. Clin Nephrol. 1991;35 Suppl 1:S31-6. [Medline].

60. Ozanne P, Francis RB, Meiselman HJ. Red blood cell aggregation in nephrotic syndrome. Kidney Int. Mar 1983;23(3):519-25. [Medline].

61. Salcedo JR, Thabet MA, Latta K, Chan JC. Nephrosis in childhood. Nephron. 1995;71(4):373-85. [Medline].

62. Southwest Pediatric Nephrology Study Group. Childhood nephrotic syndrome associated with diffuse mesangial hypercellularity. A report of the Southwest Pediatric Nephrology Study Group. Kidney Int. Jul 1983;24(1):87-94. [Medline].

63. Swaminathan S, Leung N, Lager DJ, Melton LJ 3rd, Bergstralh EJ, Rohlinger A. Changing incidence of glomerular disease in Olmsted County, Minnesota: a 30-year renal biopsy study. Clin J Am Soc Nephrol. May 2006;1(3):483-7. [Medline].

64. Tejani A, Nicastri AD, Sen D, et al. Long-term evaluation of children with nephrotic syndrome and focal segmental glomerular sclerosis. Nephron. 1983;35(4):225-31. [Medline].

65. Waldman M, Crew RJ, Valeri A, Busch J, Stokes B, Markowitz G, et al. Adult minimal-change disease: clinical characteristics, treatment, and outcomes. Clin J Am Soc Nephrol. May 2007;2(3):445-53. [Medline].

66. Warshaw BL, Hymes LC. Daily single-dose and daily reduced-dose prednisone therapy for children with the nephrotic syndrome. Pediatrics. May 1989;83(5):694-9. [Medline].

67. Wyatt RJ, Marx MB, Kazee M, Holland NH. Current estimates of the incidence of steroid responsive idiopathic nephrosis in Kentucky children 1-9 years of age. Int J Pediatr Nephrol. Jun 1982;3(2):63-5. [Medline].

68. Wynn SR, Stickler GB, Burke EC. Long-term prognosis for children with nephrotic syndrome. Clin Pediatr (Phila). Feb 1988;27(2):63-8. [Medline].

Keywords

nephrotic syndrome, nephrotic, syndrome nephrotic, nephrosis, nephropathy, proteinuria, diabetic nephropathy, glomerulosclerosis, IgA nephropathy, focal segmental glomerulosclerosis, focal glomerulosclerosis, membranous nephropathy, minimal change disease, minimal-change disease, hypoalbuminemia, hypercholesterolemia, minimal change nephropathy, pediatric nephrotic syndrome, collagen vascular disease, IgA nephropathy, amyloidosis, congenital nephrotic syndrome Finnish type, focal segmental glomerulosclerosis

Contributor Information and Disclosures

Author

Eric P Cohen, MD, Professor of Medicine, Nephrology Fellowship Program Director, Department of Medicine, Division of Nephrology, Medical College of Wisconsin; Nephrology Section Chief, Zablocki Veterans Affairs Hospital
Eric P Cohen, MD is a member of the following medical societies: American Society of Nephrology, Central Society for Clinical Research, International Society of Nephrology, and Radiation Research Society
Disclosure: Nothing to disclose.

Medical Editor

Laura L Mulloy, DO, FACP, Professor of Medicine, Chief, Section of Nephrology, Hypertension and Transplantation Medicine, Glover/Mealing Eminent Scholar Chair in Immunology, Medical College of Georgia
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Eleanor Lederer, MD, Consulting Staff, Louisville VA Hospital; Professor of Medicine; Interim Chief of Nephrology; Director of Nephrology Training Program; Director, Metabolic Stone Clinic; Director of Outpatient Clinics, Kidney Disease Program, University of Louisville School of Medicine
Eleanor Lederer, MD is a member of the following medical societies: American Association for the Advancement of Science, American Federation for Medical Research, American Society for Biochemistry and Molecular Biology, American Society for Bone and Mineral Research, American Society of Nephrology, American Society of Transplantation, International Society of Nephrology, Kentucky Medical Association, National Kidney Foundation, and Phi Beta Kappa
Disclosure: Nothing to disclose.

CME Editor

Rebecca J Schmidt, DO, FACP, FASN, Professor of Medicine, Section Chief, Department of Medicine, Section of Nephrology, West Virginia University School of Medicine
Rebecca J Schmidt, DO, FACP, FASN is a member of the following medical societies: American College of Osteopathic Internists, American College of Physicians, American Medical Association, American Society of Nephrology, International Society of Nephrology, National Kidney Foundation, Renal Physicians Association, and West Virginia State Medical Association
Disclosure: Abbott Grant/research funds Speaking and teaching; Genzyme Honoraria Consulting; Amgen Honoraria Speaking and teaching; Ortho Biotech Honoraria Speaking and teaching

Chief Editor

Vecihi Batuman, MD, FACP, FASN, Professor of Medicine, Section of Nephrology-Hypertension, Tulane University School of Medicine; Chief, Medicine Service, Southeast Louisiana Veterans Health Care System
Vecihi Batuman, MD, FACP, FASN is a member of the following medical societies: American College of Physicians, American Society of Hypertension, American Society of Nephrology, and International Society of Nephrology
Disclosure: Nothing to disclose.

Clinical guidelines:
Guidelines for the management of chronic kidney disease in HIV-infected patients: recommendations of the HIV Medicine Association of the Infectious Diseases Society of America. Infectious Diseases Society of America - Medical Specialty Society. 2005 Jun 1. 27 pages. NGC:004284

Clinical trials:
Dose-Finding Pilot Study of ACTH in Patients With Idiopathic Membranous Nephropathy (MN)

Kidney Disease Biomarkers

Permeability Factor in Focal Segmental Glomerulosclerosis

Retinoids for Minimal Change Disease and Focal Segmental Glomerulosclerosis

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