Nephrotic Syndrome

Author: Eric P Cohen, MD; Chief Editor: Vecihi Batuman, MD, FACP, FASN more...

Overview Presentation DDx Workup Treatment Medication Follow-up

Updated: Dec 20, 2010

Background Pathophysiology Epidemiology Show All

Background
Nephrotic syndrome is kidney disease with proteinuria, hypoalbuminemia, and edema. Nephrotic range proteinuria is 3 grams per day or more. On a single, "spot" urine collection, it is 2 grams of protein per gram of urine creatinine. There are many specific causes of nephrotic syndrome. These include kidney diseases such as minimal-change nephropathy, focal glomerulosclerosis, and membranous nephropathy. Nephrotic syndrome can also result from systemic diseases that affect other organs in addition to the kidneys, such as diabetes, amyloidosis, and lupus erythematosus. A schematic drawing of the glomerular barrier is shown below.

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 (Qp) 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 may affect adults and children, of both sexes and of any race. It may occur in typical form, or in association with nephritic syndrome. The latter connotes glomerular inflammation, with hematuria and impaired kidney function.

Classification
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.

Recent studies
In a retrospective study, Vivarelli et al investigated whether, in children with idiopathic nephrotic syndrome, the period of time between the onset of steroid therapy and syndrome remission can serve as a prognostic indicator. The study included 103 patients with idiopathic nephrotic syndrome and had a median follow-up time of 43 months. The authors found that in patients who did not suffer relapse or who relapsed infrequently, the median period between treatment onset and remission was less than 7 days. In patients who frequently relapsed or who developed steroid-dependent nephrotic syndrome, the median time to remission was more than 7 days after treatment began. The authors concluded that the length of time between steroid treatment onset and remission is an early prognostic indicator for patients with idiopathic nephrotic syndrome.[6]

Pathophysiology
Glomerular permeability
In a healthy individual, less than 0.1% of plasma albumin may traverse the glomerular filtration barrier.[7] 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.[8] 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.[9] 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 structuresthe fenestrated endothelium, glomerular basement membrane, and glomerular epitheliumare the glomerular filtration barrier. A schematic drawing of the glomerular barrier is seen in the image below.

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 (Qp) 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). 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:

Qw = K ([Pc - Pi] - [pp - pi] In this formula, Qw is net flux of water, K is the capillary filtration coefficient, Pc is capillary hydrostatic pressure, and Pi is the interstitial fluid hydrostatic pressure, while pp is the plasma oncotic pressure, and pi 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.[10] 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.[11] 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%.[12] Vitamin Dbinding protein may be lost in the urine, leading to hypovitaminosis D, with malabsorption of calcium and development of bone disease.[13] Urinary immunoglobulin losses may lower the patient's resistance to infections and increase the risk of sepsis and peritonitis.

Epidemiology
Frequency

United States

The figure below shows the incidence per million population of important causes of nephrotic syndrome. Diabetic nephropathy with nephrotic syndrome is most common, at an estimated rate of at least 50 cases per million population. That is an underestimation, however, since the rate of end-stage renal disease from diabetes has reached 100 cases per million population in some Western countries. In children, nephrotic syndrome may occur at a rate of 20 cases per million children.[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. 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.[14, 15] 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.[16] Glomerular disease may be associated with schistosomal infection, as could occur in Egypt.[17] 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.[18] 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 parasiteassociated nephrotic syndrome in the Congo.[19, 20] 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.[20]

Mortality/Morbidity

In the preantibiotic era, infection was a major factor in the mortality rate among patients with nephrotic syndrome.[21] 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.[22] 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.[23]

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.[24]

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.[25] Focal glomerulosclerosis appears to be overrepresented in African American children, as compared with white children, as a cause of nephrotic syndrome.[26]

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.[27] However, lupus nephritis affects mostly women.

Age
The image below shows typical ages at which a given cause of nephrotic syndrome may occur. It does not show every possible cause of nephrotic syndrome, such as lupus nephritis, which typically affects young black women. The ages shown are averages.

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

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).[28] 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

oncologists 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.[27] 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. Previous Proceed to Differential Diagnoses [ CLOSE WINDOW ]

Differentials

Diabetic Nephropathy Focal Segmental Glomerulosclerosis Glomerulonephritis, Acute Glomerulonephritis, Chronic Glomerulonephritis, Membranous HIV Nephropathy IgA Nephropathy Light Chain-Associated Renal Disorders Minimal-Change Disease Nephritis, Radiation Sickle Cell Nephropathy

Laboratory Studies

Urinalysis is the first test used in the diagnosis of nephrotic syndrome. o 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. o Glucosuria points to diabetes. o The urine sediment exam may show cells and/or casts. o 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. o 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. o 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.[29] 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.[30]

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.[31]

Procedures

For childhood nephrotic syndrome, a renal biopsy is indicated for the following: o Congenital nephrotic syndrome o Children older than 8 years at onset o Steroid resistance o Frequent relapses or steroid dependency o 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 o 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.[8]

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

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. These are detailed in the chapters specific to each of these. Thus, glucocorticosteroids, such as prednisone, are used for minimal-change nephropathy. In children, relapse after successful use of prednisone or lack

of response to prednisone ("resistance") may be treated by use of rituximab, an antibody against B-cells. Rituximab has also been used in membranous nephropathy in adults.[32] 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.

Nephrotic Syndrome Medication

Author: Eric P Cohen, MD; Chief Editor: Vecihi Batuman, MD, FACP, FASN more...

Overview Presentation DDx Workup Treatment Medication

Follow-up

Updated: Dec 20, 2010

Medication Summary Corticosteroids Immunomodulators Immunosuppressants Diuretics Angiotensin-converting Enzyme (ACE) Inhibitors Angiotensin II Receptor Antagonist Show All

Medication Summary
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
Class Summary
Have anti-inflammatory properties and modify the body's immune response to diverse stimuli. View full drug information

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.

Immunomodulators
Class Summary
These agents regulate key steps of the immune system. View full drug information

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. View full drug information

Cyclosporine (Sandimmune, Neoral, Gengraf)

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

Rituximab (Rituxan)

Chimeric humanized murine monoclonal antibody against CD20 antigen found on surface on lymphocytes.

Immunosuppressants
Class Summary
Inhibit key steps that mediate immune reactions.[33, 34] View full drug information

Mycophenolate (CellCept, Myfortic)

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

Diuretics
Class Summary
Used for symptomatic treatment of edema. View full drug information

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. View full drug information

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.

Angiotensin-converting Enzyme (ACE) Inhibitors

Class Summary
These agents improve hypertension by inhibiting renin or angiotensin II production. View full drug information

Lisinopril (Prinivil, Zestril)

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

Angiotensin II Receptor Antagonist

Class Summary

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

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.

Further Outpatient Care

Long-term management o 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. o 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. o 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 steroidresistant 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. Rituximab has been effective in some cases of nephrotic syndrome that relapse after prednisone treatment or in cases that "resist" prednisone treatment.[35] This drug is a chimeric murine/human antibody against the CD20 antigen of B cells. It presumably exerts its benefit by suppressing antibody production. Its effect to suppress the immune system cannot be ignored.

Deterrence/Prevention
Amniocentesis may show high levels of alpha-fetoprotein when the fetus has congenital nephrotic syndrome of the Finnish type.[36] 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.[37] 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.[38] 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.[39] 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.[13] A further complication derives from therapies, especially prednisone use. Low bone mass may be found, in relation to cumulative steroid dose.[40] 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.[41] 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.[12] 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.

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.[37] 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.[38] 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.[39] 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.[13] A further complication derives from therapies, especially prednisone use. Low bone mass may be found, in relation to cumulative steroid dose.[40] 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.[41] 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.[12] 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. o 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. o Poor patient response to steroid therapy may predict a poor outcome, and children who present with hematuria and hypertension are more likely to be steroidresistant and have a poorer prognosis than are those who do not present with these conditions. o In adult nephrotic syndrome, there is a similar variability according to the underlying cause. o 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. o As noted, the prognosis of membranous nephropathy is good in terms of patient survival, being the same as that of the unaffected population. o 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. o 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 o 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. o Progression to renal failure will require preparation for dialysis and/or kidney transplantation. Adult nephrotic syndrome o Forms of nephrotic syndrome that cannot be cured may evolve into renal failure and the need for dialysis or kidney transplantation.

Contributor Information and Disclosures

Author
Eric P Cohen, MD Professor, 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.

Specialty Editor Board

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. Francisco Talavera, PharmD, PhD Senior Pharmacy Editor, eMedicine Disclosure: eMedicine Salary Employment Eleanor Lederer, MD Professor of Medicine; Chief, Nephrology Division; Director, Nephrology Training Program; Director, Metabolic Stone Clinic, Kidney Disease Program, University of Louisville School of Medicine; Consulting Staff, Louisville Veterans Affairs Hospital 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.

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 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; AMAG Honoraria Speaking and teaching; Amgen Honoraria Speaking and teaching; Ortho Biotech Honoraria Speaking and teaching; Renal Ventures Ownership interest Other

Chief Editor
Vecihi Batuman, MD, FACP, FASN Professor of Medicine, Section of NephrologyHypertension, 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. [CLOSE WINDOW]

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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 (Qp) 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). 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. A schema of the average patient ages associated with various common forms of nephrotic syndrome. [CLOSE WINDOW] [CLOSE WINDOW] Read more about Nephrotic Syndrome on Medscape Related Reference Topics

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