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Nephrotic syndrome

Nephrotic syndrome
Revised: 08 Jan 2013 Last Updated: 07 Jan 2013 Copyright Elsevier BV. All rights reserved.

Key points
Nephrotic syndrome is characterized by high protein excretion, peripheral edema, and metabolic abnormalities Consists of clinical and laboratory abnormalities common to several primary and secondary kidney diseases, each characterized by increased permeability of the glomerular capillary wall to circulating plasma proteins, particularly albumin The most common primary cause in children is minimal change glomerulopathy; in adults, it is idiopathic membranous glomerulopathy Presents with edema, hypoalbuminemia, massive proteinuria (3.5 g or greater per 24 hours), hypertension , and hyponatremia Hyperlipidemia , lipiduria, and hypercoagulability typically are also present Diagnosis usually requires a renal biopsy to identify the histopathologic type of renal involvement causing massive proteinuria A significant proportion of adults who show signs of nephrotic syndrome have a related systemic disease, such as diabetic glomerulosclerosis , amyloidosis , systemic lupus erythematosus (SLE), or HIVassociated nephropathy Urgent action: Urgently refer or admit patients with acute kidney injury or rapidly deteriorating renal function Urgently refer or admit patients with nephrotic crisis (as evidenced by massive edema, anorexia, vomiting, pleural effusions , muscle wasting, and pulmonary embolism ) In patients with volume overload, order immediate blood tests, including sodium, potassium, chloride, carbon dioxide, blood urea nitrogen (BUN), creatinine, albumin, spot urine protein, and albumin-tocreatinine ratio, to assess the degree of proteinuria Obtain a chest radiograph to rule out pulmonary edema Order more advanced blood tests, such as hepatitis A, B, and C; cytoplasmic antineutrophil cytoplasmic antibody (c-ANCA); perinuclear antineutrophil cytoplasmic antibody (p-ANCA); lupus antibody; HIV; and C3 and C4 complement levels Insert intravenous lines and assess for volume status; if the patient is volume overloaded, start treatment with powerful loop diuretics such as furosemide Most of the time, patients can be treated with medication alone and do not require dialysis In patients with severe volume overload, treatment may have to be given in the intensive care unit, with frequent monitoring of electrolytes

Background
Description

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Nephrotic syndrome with proteinuria, hypoalbuminemia, and edema results from either a primary glomerular disorder (idiopathic nephrotic syndrome) or is a manifestation of systemic disease (in 30%-50% of cases in adults) Renal biopsy in idiopathic nephrotic syndrome in adults usually shows one of four pathologies: membranous glomerulonephropathy (30%-40% of idiopathic cases), focal segmental glomerulosclerosis (FSGS) (20%-30%), minimal change disease (10%-15%), or membranoproliferative glomerulonephritis (10%-20%) Membranous glomerulonephropathy has a fair prognosis if treated early and appropriately Most common associated multisystem diseases are diabetes mellitus (by far the most common), SLE and other collagen vascular diseases, and primary or secondary amyloidosis , especially in older patients HIV infection is associated with a specific HIV nephropathy Proteinuria in nephrotic syndrome is due to increased permeability of the glomerular basement membrane to albumin and arises in response to alterations in both the size and charge barriers of the glomerular filtration apparatus. Albumin is the predominant protein excreted Membranoproliferative glomerulonephritis, poststreptococcal glomerulonephritis , and Alport syndrome typically manifest with both nephrotic syndrome and nephritic syndrome , which manifests with hematuria, erythrocyte casts, and proteinuria that may or may not be in the nephrotic range Hypoalbuminemia seems to be due to failure of hepatic synthesis of albumin to compensate for the albumin lost in urine. Release of cytokines may also suppress hepatic albumin synthesis Edema develops when plasma oncotic pressure decreases because the proteinuria causes a decrease in serum albumin concentration. This causes fluid to move from the vascular fluid compartment to the interstitial fluid compartment, initiating a series of pathophysiologic events that results in renal sodium retention and generalized edema. Edema may be massive and widely distributed, and it may vary with posture. Facial and upper-limb edema is characteristic and particularly obvious after recumbency. Transudative ascites and pleural effusions are often seen An increase in serum cholesterol and phospholipid levels and lipiduria are typically components of nephrotic syndrome. This is due to increased hepatic synthesis, which may be triggered by the decrease in plasma oncotic pressure Many patients with nephrotic syndrome have other metabolic derangements, including a hypercoagulable state, possibly due to urinary loss of antithrombin III and decreased activity of proteins S and C. Loss of vitamin Dbinding globulin may result in vitamin D deficiency , hypocalcemia , osteomalacia , and secondary hyperparathyroidism . Loss of immunoglobulins may result in impaired immunity and increased rates of infections. Depletion of transferrin may result in iron-deficiency anemia A rapid diagnostic and confirmatory test for nephrotic-range proteinuria is the random urine protein-tocreatinine ratio, which gives a fairly close estimate of 24-hour urine collection. It is calculated as urinary protein in milligrams divided by urinary creatinine in milligrams, multiplied by 1,000 in men and by 800 in women. The result of this calculation is expressed in grams of protein per day. This test can also be used as an outpatient guide to therapy Always perform a kidney biopsy if the patient has no contraindications, such as a bleeding diathesis or advanced renal failure ; this is the gold standard for the correct diagnosis and the best guide to therapy. Do not hesitate to repeat the biopsy if the response is not as expected or if the patient's condition worsens

Epidemiology
Incidence: Children: 2 per 100,000 persons per year Adults: 3 to 4 per 100,000 persons per year

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Demographics: Minimal change disease accounts for more than 80% of all cases of nephrotic syndrome in children younger than 10 years but only 10% to 15% of primary cases in adults Minimal change disease affects boys twice as frequently as girls, but the gender ratio is equal in adults FSGS is the predominant cause of nephrotic syndrome in African American persons Familial renal diseases such as Alport syndrome , nail-patella syndrome, and congenital nephrotic syndrome may cause nephrotic syndrome Reflux nephropathy has a strong familial component and may cause renal failure with nephrotic syndrome

Causes and risk factors

Common causes Nephrotic syndrome is either primary (idiopathic) or secondary to another condition or disorder such as diabetes mellitus or viral hepatitis C . It is helpful to approach the etiology of nephrotic syndrome as 'caused by' a histopathologic type, as delineated below, since common histopathologies are associated with a similar coexisting condition, clinical features, treatments and prognoses. Minimal change glomerulopathy: Accounts for 80% of cases of nephrotic syndrome in children younger than 10 years, approximately 50% of cases in older children, and 10% to 15% of cases in adults. However, incidence of minimal change glomerulopathy in children is decreasing due to an increasing incidence of FSGS Minimal change disease has an excellent prognosis with corticosteroid therapy; in fact, a trial of corticosteroids can be used as a diagnostic test No specific cause is found in most patients. The disease is immunologically mediated and related to abnormal T-cell function rather than to immune-complex deposition Patients usually present with full-blown pure nephrotic syndrome Hypertension and microscopic hematuria are uncommon, but one of these may occur in 20% to 30% of patients Renal impairment and acute kidney injury can occur but are rare Severe edema, ascites, and pleural effusions may develop Spontaneous remission may occur in rare cases, but it is seldom justified to leave the patient untreated because persistent nephrotic syndrome causes significant morbidity and mortality The risk of relapse decreases with time; relapse is often precipitated by a minor upper respiratory tract infection Nonsteroidal anti-inflammatory drugs (NSAIDs) or sulfasalazine and its derivatives may cause minimal change disease in adults. This medication history needs to be elicited during examination Although usually idiopathic, may also be caused by mercury or lead exposure ; Hodgkin disease ; cancer; food allergies; infectious mononucleosis ; and HIV infection FSGS: Important entity associated with primary nephrotic syndrome in adults and children; forms part of a spectrum that ranges from minimal change to corticosteroid-resistant FSGS Primary FSGS accounts for 10% to 15% of cases of nephrotic syndrome in children and as many as 35% of cases in adults
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Incidence seems to be increasing, particularly in African American males but also in the white population Poor prognosis with high rate of progression to end-stage renal disease in more than 80% untreated cases Presents with proteinuria, often full-blown nephrotic syndrome, impaired or deteriorating renal function, and hypertension in 30% to 50% of patients. Proteinuria is unselective Spontaneous remission is rare Secondary FSGS is the final result of many different causes of glomerular injury, including late-stage focal glomerulonephritis, renal dysplasia, reflux nephropathy, surgical loss of renal mass, sickle cell disease , obesity , cyanotic heart disease, heroin abuse , HIV-associated nephropathy , sleep apnea , and aging. Prognosis is determined by the underlying condition Mutation in several genes encoding the podocyte protein have been identified as a possible cause of FSGS 20% to 30% of patients have underlying disease Membranous nephropathy: Most common clinicopathologic entity associated with idiopathic nephrotic syndrome in adults May be primary or secondary to a wide range of diseases. Its pathogenesis is unknown, and treatment is controversial 80% of patients present with nephrotic syndrome, and the remainder present with lesser degrees of proteinuria. Occasionally, patients may present with acute kidney injury as a complication of nephrotic syndrome Up to 50% of patients are hypertensive at presentation Contributing factors can include tumors (15% of cases; proportion increases with age); drugs, especially gold and penicillamine; infection with hepatitis B , syphilis , or malaria ; SLE ; and sickle cell disease Membranoproliferative glomerulonephritis: Group of immune complex diseases: type 1 (mesangiocapillary glomerulonephritis); type 2 (dense deposit disease), with characteristic histologic appearance that may be idiopathic or caused by another disease ( eg , hepatitis C or cryoglobulinemia) Both types usually present with mixed nephrotic and nephritic syndrome ; urine sediment contains nephritic components such as hematuria and erythrocyte casts, as well as evidence of lipiduria (oval fat bodies) associated with nephrotic-range proteinuria Hypertension is common Up to 30% of patients present with rapidly deteriorating renal function Slow progression to end-stage renal disease is the usual course Spontaneous remission is rare Contributing factors can include SLE; mixed essential cryoglobulinemia; cryoglobulinemia secondary to chronic infection, including hepatitis C, subacute bacterial endocarditis , or HIV; homozygous for sickle cell trait; intravenous drug abuse; partial lipodystrophy; and cancer and chronic lymphocytic leukemia Secondary causes The most common multisystem diseases found in conjunction with nephrotic syndrome are diabetes mellitus; SLE and other collagen vascular diseases; chronic antigenemic states, such as cancer ( eg , lymphomas); malaria, and primary or secondary amyloidosis . Diabetic glomerulosclerosis due to either diabetes mellitus type 1 or type 2 is the most common systemic disease causing nephrotic syndrome

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SLE with renal involvement may occasionally present with nephrotic syndrome and the morphology of membranous glomerulopathy on renal biopsy Amyloidosis causes proteinuria, nephrotic syndrome, and progressive renal failure Carcinomas produce features typical of membranous glomerulonephropathy, implicating an immune response to tumor antigens; lymphomas and leukemias are more often associated with minimal change disease; multiple myeloma is associated with nephrotic syndrome due to amyloidosis Other multisystem disorders include cryoglobulinemia and sarcoidosis Chronic hepatitis C infection may be the most common infectious condition associated with nephrotic syndrome or nephritic syndrome and membranoproliferative glomerulonephritis. HIV infection can cause a glomerular lesion that resembles FSGS; it usually leads to nephrotic syndrome and can cause rapidly progressive renal failure. Other associated infections include poststreptococcal nephritis , infective endocarditis, syphilis, and hepatitis B (typically the lesion is membranous) Analgesics, NSAIDs, gold, penicillamine, aminoglycosides, cisplatin, and captopril are all implicated in nephrotic syndrome Hereditary disorders, mainly sickle cell disease, nail-patella syndrome, and congenital nephrotic syndrome, can cause microscopic hematuria Preeclampsia Recurrence of primary disease in a renal transplant recipient, usually FSGS causing mostly subnephrotic proteinuria Protozoan and helminthic infections acquired during travel to endemic areas may be implicated in nephrotic syndrome

Screening
Not applicable.

Primary prevention
Not applicable.

Diagnosis
Summary approach
Nephrotic syndrome is a clinical diagnosis confirmed by the finding of protein excretion of 3.5 g or greater per 24 hours on laboratory investigation In most cases, renal biopsy is needed to make a definitive diagnosis (except in children, patients with diabetes , and patients with obvious end-stage renal disease), such as glomerulonephritis or amyloidosis Associated disorders may require further appropriate investigation

Clinical presentation
Symptoms: Some patients may have nephrotic-range proteinuria but no symptoms until edema develops Swelling of the hands, feet, and face Abdominal fullness Weight gain
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Symptoms of contributory disease in secondary nephrotic syndrome Weakness, tiredness Excessive frothing of urine Other historical information: Patients may be asymptomatic, and proteinuria is detected incidentally Weight gain may occur with fluid retention Severe peripheral edema may occur Ascites may lead to a feeling of abdominal fullness Exertional dyspnea may occur with pleural effusion . Pulmonary edema may occur in patients with very low serum albumin levels A history of kidney disease ( eg , vesicoureteral reflux, amyloidosis ), urologic surgery ( eg , nephrectomy), and systemic diseases such as diabetes mellitus , collagen vascular diseases, chronic infections, malignancy, and amyloidosis may be associated with nephrotic syndrome Familial renal diseases, such as Alport syndrome , nail-patella syndrome, and congenital nephrotic syndrome, may cause nephrotic syndrome. Reflux nephropathy has a strong familial component and may cause renal failure with nephrotic syndrome. Analgesics, NSAIDs, gold, penicillamine, aminoglycosides, cisplatin, and captopril are all implicated in nephrotic syndrome Exposure to organic solvents may increase risk of glomerulonephritis. Heavy metals, such as cadmium and lead, are nephrotoxic People with diabetes who smoke are more likely to have renal disease Injection drug use is the most important risk factor for hepatitis C infection and increases the risk for other blood-borne infections, such as viral hepatitis B and HIV Protozoan and helminthic infections acquired during travel to endemic areas may be implicated in nephrotic syndrome Signs: Hypertension : Severe hypertension is unusual in minimal change disease; often accompanies nephrotic syndrome and some degree of renal insufficiency in FSGS Edema, which may be severe; facial edema that is most marked in the morning is characteristic, particularly in children Ascites Pleural effusions Infections, especially with gram-positive bacteria ( eg , as in pneumonia) Deep vein thrombosis Other physical examination factors: General examination may show nonspecific signs associated with renal insufficiency: white nails, pallor, increased skin pigmentation Assessment of fluid overload: look for pitting edema, particularly in dependent areas. Because intravascular volume is likely to be decreased, jugular vein pressure is not usually elevated, and orthostatic hypotension may be present
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Assessment for signs related to underlying disorder

Diagnostic testing
Routine studies and tests that can likely be done in a primary care setting or hospital include complete blood count ; renal function (BUN and creatinine); biochemical profile (serum electrolytes, serum albumin, total protein, cholesterol); urinalysis ; and chest radiography Renal function and abnormalities in proteinuria can be assessed by creatinine clearance, 24-hour urine collection for protein , and serum and urine electrophoresis Tests likely to be requested by a specialist to help identify underlying cause include special immunologic tests ( eg , hepatitis serology, antinuclear antibodies [ANA], antidouble-stranded DNA antibodies, serum complement levels [C3, C4, CH50], c-ANCA and p-ANCA, and HIV antibodies), renal biopsy , and renal ultrasonography Complete blood count Renal function Biochemical profile Urinalysis 24-hour urine collection for protein Special immunologic tests Renal biopsy Chest radiography Renal ultrasonography

Differential diagnosis
It is important to differentiate nephrotic syndrome from nephritic syndrome , which manifests with hematuria, erythrocyte casts, and proteinuria that may or may not be in the nephrotic range (3.5 g or greater per 24 hours). Membranoproliferative glomerulonephritis often manifests with nephrotic syndrome, but there is almost always a concomitant nephritic syndrome. Edematous states without proteinuria

Consultation
After infection has been excluded, all patients with unexplained massive proteinuria should be referred to a nephrologist to develop a plan for diagnosis and therapy, including possible renal biopsy .

Treatment
Summary approach
Goals: To treat the manifestations (proteinuria, edema, hyperlipidemia ) and, if necessary, the complications of nephrotic syndrome To provide specific treatment as indicated, depending on underlying or associated disease To preserve or improve renal function, especially with assiduous blood pressure control to minimize the rate of progression of renal failure To reduce the risk for complications of nephrotic syndrome, such as with antithrombotic or antibiotic prophylaxis Immediate action: Patients with acute kidney injury with rapidly deteriorating renal function need urgent hospital assessment
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Patients with complicating severe infections ( eg , peritonitis complicating ascites, septicemia ) require urgent hospitalization and critical care Summary of therapies: Treatment can be considered symptomatic, supportive, or specific to the underlying condition. Specific therapeutic regimens depend on findings from renal biopsy , degree of renal dysfunction, and associated conditions and etiologies Corticosteroids, such as prednisone , are the mainstay of treatment for minimal change disease in children and adults. In patients with membranous glomerulopathy and FSGS, corticosteroids are also commonly used initially, but with less consistent positive results, and longer periods of administration are required. Corticosteroids alone may hasten remission in some patients with membranous nephropathy In patients with corticosteroid failure or dependence, immunosuppressive therapy with cytotoxic agents has been used with varying results. They are often used as corticosteroid-sparing agents and include cyclophosphamide , cyclosporine , azathioprine , mycophenolate mofetil , and chlorambucil (used rarely in adults). Some of these agents may be helpful in preventing relapse in children with corticosteroid-sensitive nephritic syndrome , although the effect may not be long-lasting. Tacrolimus is a newer agent used in transplantation that may be useful in resistant cases, but this is still experimental. Evidence is insufficient to support the use of specific immunosuppressive or other potent agents in membranoproliferative glomerulonephritis. Such therapy should not be attempted without prior consultation with an experienced nephrologist A Cochrane review of small studies from China found some evidence of possible effectiveness of intravenous immunoglobulin and Chinese medicine herbs in preventing infection in children with nephrotic syndrome, but these therapies are not routinely recommended Other considerations: Edema may be controlled with loop diuretics (such as in heart failure ), but hypovolemia may precipitate renal failure in nephrotic patients. Intravenous treatments with albumin or loop diuretic infusion may also be of use in a hospital setting under supervision by a nephrologist Angiotensin-converting enzyme (ACE) inhibitors and angiotensin-II receptor blockers (ARBs) may reduce proteinuria and are especially useful for hypertension . High blood pressure should be vigorously treated, because effective control may slow the rate of progression of renal failure irrespective of underlying cause Prophylactic anticoagulants may be indicated for severely nephrotic patients because a hypercoagulable state exists, but long-term anticoagulation should not be necessary if the underlying condition can be put into remission ( eg , minimal change disease). However, patients with nephrotic syndrome may be relatively resistant to effects of heparin as a result of antithrombin III losses in the urine Antibiotic prophylaxis has been used in patients with severe nephrotic syndrome, although evidence of its effectiveness is lacking. Prophylactic penicillin may be considered in patients with ascites, since they are at risk for spontaneous pneumococcal peritonitis Hypercholesterolemia may need to be controlled with statins, especially if the underlying condition is incurable. An association between hyperlipidemia of nephrotic syndrome and accelerated atherosclerosis has not been proven conclusively. Dietary manipulations are ineffective in nephrotic syndrome owing to severity of hyperlipidemia A low-sodium, normal-protein diet may be appropriate for nephrotic patients Chronic kidney disease and end-stage renal disease will be the outcome for some patients (more likely in adults than children) despite therapy, depending on the underlying lesion in the kidney. These conditions are more likely in nephrotic patients with morphologic glomerular abnormalities on renal biopsy ( eg , membranous glomerulopathy, FSGS, membranoproliferative glomerulonephritis)

Medications
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Prednisone

Non-drug treatments
Diet

Special circumstances
Children: Corticosteroids are the mainstay of treatment Use of alkylating agents in children with corticosteroid-responsive disease is controversial. These agents are probably required if the corticosteroid dose is likely to interfere with growth (>0.5 mg/kg on alternate days) Cyclophosphamide (2-2.5 mg/kg/day) for 8 weeks is effective at producing longer-lasting remissions Chlorambucil (0.2 mg/kg/day) for 2 months seems to have an effect similar to that of cyclophosphamide Cyclosporine (up to 150 mg/m2/day) is usually effective in nephrotic children who have frequent relapse. Relapse is almost invariable within 3 months of stopping treatment, and there is a risk of cyclosporine nephrotoxicity

Consultation
Preferably, all patients should be referred to a nephrologist for supervision of treatment Patients with refractory edema may need admission for possible intravenous diuretic/ intravenous albumin therapy and other special measures as recommended by renal consultants Patients with corticosteroid-resistant disease may need cytotoxic therapy and hospital admission

Follow-up
Long-term follow-up is required while the patient remains proteinuric Specific associated diseases may also require long-term follow-up Prognosis Depends on the underlying cause of nephrotic syndrome and prognosis of any associated disorder Minimal change disease: Relapsing course In children, approximately 30% of those who respond to corticosteroids never have a relapse, and another 10% to 20% are cured after one to four episodes that are responsive to corticosteroids. The remainder of patients are considered 'frequent relapsers' Young adults tend to have relapse less frequently than do children Overall prognosis for eventual complete remission is excellent FSGS: Traditionally thought to have a poor prognosis 30% to 40% of patients respond to corticosteroids with complete remission; in those who do respond, renal survival at 5 years exceeds 95% Even in patients who do not experience remission, renal survival at 5 years is 55%
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Remission of proteinuria in FSGS is associated with a greatly reduced risk of progressive renal disease Membranous nephropathy: Clinical course is unpredictable Sustained remission may occur after years of nephrotic-range proteinuria; 20% to 30% of patients have spontaneous remission, and up to 40% have partial remission or remain stable Renal function may start to decline and then improve, although more commonly the decline to end-stage renal disease is inexorable once it has started. Renal failure eventually develops in 15% to 20% of patients Persistent nephrotic syndrome causes profound muscle wasting and malaise Prognosis is poorer for patients with cancer-associated nephrotic syndrome than for patients with cancer but no nephrotic syndrome Risk factors for poor prognosis are male sex, age older than 50 years, and heavy proteinuria Risk of recurrence of disease in renal transplant is approximately 10% Membranoproliferative glomerulonephritis: End-stage renal disease occurs in 50% of patients at 10 years and 90% at 20 years Spontaneous remission occurs in less than 20% of patients Factors affecting prognosis Poor prognosis: Heavy proteinuria, lack of response to therapy Male, age, smoking , hypertension Systemic disorders such as diabetes mellitus , hepatitis, or cancer Fair prognosis: Rapid response to treatment Treatable systemic diseases such as malaria or syphilis Progression of disease Recurrent and progressive disease is characterized by persistent heavy proteinuria and a gradual elevation in the plasma creatinine concentration over a period of years. Some patients, however, develop an acute decline in renal function, and additional disorders should be identified Recurrence of FSGS is significant, since it can recur in up to 20% of patients who have had a kidney transplant Membranous glomerulonephritis is also most likely to recur after a remission Relapses are treated similarly to initial presentation Children who have frequent relapse may be managed by gradually tapering the corticosteroid dose to the threshold at which relapse occurs and continuing this dose for 6 to 12 months. Safety depends on the dose of corticosteroid required Cytotoxic drugs may be considered for patients who do not respond to corticosteroids Patients who progress to end-stage renal disease require dialysis or renal transplant for survival Clinical complications
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Renal vein thrombosis is an important and often underdiagnosed cause of renal impairment in patients with nephrotic syndrome. It is frequently caused by membranous nephropathy, lupus nephritis, amyloidosis , and any form of glomerulonephritis that causes nephrotic syndrome. It may be completely asymptomatic or cause loin pain, hematuria, renal swelling, acute kidney injury, or acute or chronic kidney disease with oliguria. If it extends to the vena cava, it may cause bilateral leg swelling or pulmonary embolism . Thrombosis of the renal vein or its branches may be found in up to 50% of patients with membranous nephropathy and nephrotic syndrome but is symptomatic in only 5% to 15% Hypercholesterolemia : Greatly increased serum cholesterol is nearly always seen in nephrotic patients, and patients with a history of nephrotic syndrome have an increased risk of death from coronary heart disease. The mechanism is uncertain, although increased hepatic synthesis seems to be switched on by decreased plasma oncotic pressure. Dietary treatment is usually disappointing; statins are effective and are the drugs of choice Infection: Spontaneous bacterial peritonitis occurs particularly in nephrotic children and is frequently due to pneumococci. Cellulitis is a frequent problem in adults Acute kidney injury with hypovolemia occasionally occurs, especially in adults after treatment with diuretics Chronic kidney disease may develop and progress to end-stage renal disease Growth retardation is a potential complication in children treated with long-term corticosteroids

Patient education
A large percentage of patients with nephrotic syndrome are children Nephrotic syndrome is often a chronic, relapsing-remitting disease requiring long-term treatment Depending on etiology and response to therapy, nephrotic syndrome may result in end-stage renal disease requiring dialysis or transplant

Online information for patients

Mayo Clinic: Nephrotic syndrome National Kidney and Urologic Diseases Information Clearinghouse: Childhood nephrotic syndrome Nephrotic syndrome in adults

Resources
Summary of evidence
Evidence Increased duration and dose of corticosteroids is associated with a reduced risk of relapse in children with corticosteroid-sensitive nephrotic syndrome. A systematic review of 24 RCTs evaluating 1,726 children with corticosteroid-sensitive nephrotic syndrome found an inverse linear relationship between the duration of treatment in the first episode and the risk of relapse. This reduction in risk was associated with both an increase in duration and an increase in dose. The reviewers concluded that children in their first episode should receive at least 3 months of corticosteroid treatment, and that there was an increase in benefit for up to 7 months of treatment. During daily therapy, a single daily dose was as effective as divided doses, and therapy every second day was more effective than intermittent therapy in maintaining remission. In relapsing disease, long-duration therapy every second day was more effective than standard-duration therapy. The reviewers concluded that increased therapy was not associated with increases in adverse events. [1] Level of evidence: 1
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An RCT involving 40 children aged 1.5 to 13.2 years showed that in children with nephrotic syndrome who are receiving alternate-day corticosteroids and who develop a respiratory infection, prescribing a course of daily corticosteroids may prevent relapse of nephrotic syndrome. [2] Level of evidence: 1 References

References
Evidence references [1] Hodson EM, Willis NS, Craig JC. Corticosteroid therapy for nephrotic syndrome in children. Cochrane Database Syst Rev. 2007;CD001533. CrossRef [2] Abeyagunawardena AS, Trompeter RS. Increasing the dose of prednisolone during viral infections reduces the risk of relapse in nephrotic syndrome: a randomised controlled trial. Arch Dis Child. 2008;93:226-8 CrossRef Guidelines The National Kidney Foundation has produced the following: National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification . Am J Kidney Dis. 2002;39:S1-S266 Further reading Bonilla-Felix M, Parra C, Dajani T, et al. Changing patterns in the histopathology of idiopathic nephrotic syndrome in children. Kidney Int. 1999;55:1885-90 Braun N, Schmutzler F, Lange C, Perna A, Remuzzi G, Willis NS. Immunosuppressive treatment for focal segmental glomerulosclerosis in adults. Cochrane Database Syst Rev. 2008:CD003233 Chen A, Frank R, Vento S, et al. Idiopathic membranous nephropathy in pediatric patients: presentation, response to therapy, and long-term outcome. BMC Nephrol. 2007;8:11 Chen M, Li H, Li XY, et al; Chinese Nephropathy Membranous Study Group. Tacrolimus combined with corticosteroids in treatment of nephrotic idiopathic membranous nephropathy: a multicenter randomized controlled trial. Am J Med Sci. 2010;339:233-8 Eddy AA, Symons JM. Nephrotic syndrome in childhood. Lancet. 2003;362:629-39 Eknoyan G, Hostetter T, Bakris GL, et al. Proteinuria and other markers of chronic kidney disease: a position statement of the National Kidney Foundation (NKF) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Am J Kidney Dis. 2003;42:617-22 Fakhouri F, Bocquet N, Taupin P, et al. Steroid-sensitive nephrotic syndrome: from childhood to adulthood. Am J Kidney Dis. 2003;41:550-7 Filler G, Young E, Geier P, Carpenter B, Drukker A, Feber J. Is there really an increase in non-minimal change nephrotic syndrome in children? Am J Kidney Dis. 2003;42:1107-13 Glassock RJ. Diagnosis and natural course of membranous nephropathy. Semin Nephrol. 2003;23:324-32 Hodson EM, Willis NS, Craig JC. Interventions for idiopathic steroid-resistant nephrotic syndrome in children. Cochrane Database Syst Rev. 2010:CD003594 Hodson EM, Willis NS, Craig JC. Non-corticosteroid treatment for nephrotic syndrome in children. Cochrane Database Syst Rev. 2008:CD002290 Hogg RJ. Adolescents with proteinuria and/or the nephrotic syndrome. Adolesc Med Clin. 2005;16:163-72 Hogg RJ, Furth S, Lemley KV, et al; National Kidney Foundation's Kidney Disease Outcomes Quality Initiative. National Kidney Foundation's Kidney Disease Outcomes Quality Initiative clinical practice guidelines for chronic kidney disease in children and adolescents: evaluation, classification, and stratification. Pediatrics. 2003;111:1416-21
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Hogg RJ, Portman RJ, Milliner D, Lemley KV, Eddy A, Ingelfinger J. Evaluation and management of proteinuria and nephrotic syndrome in children: recommendations from a pediatric nephrology panel established at the National Kidney Foundation conference on proteinuria, albuminuria, risk, assessment, detection, and elimination (PARADE). Pediatrics. 2000;105:1242-9 Palmer SC, Nand K, Strippoli GF. Interventions for minimal change disease in adults with nephrotic syndrome. Cochrane Database Syst Rev. 2008:CD001537 Perna A, Schieppati A, Zamora J, Giuliano GA, Braun N, Remuzzi G. Immunosuppressive treatment for idiopathic membranous nephropathy: a systematic review. Am J Kidney Dis. 2004;44:385-401 Ponticelli C, Passerini P. Other immunosuppressive agents for focal segmental glomerulosclerosis. Semin Nephrol. 2003;23:242-8 Schieppati A, Perna A, Zamora J, Giuliano GA, Braun N, Remuzzi G. Immunosuppressive treatment for idiopathic membranous nephropathy in adults with nephrotic syndrome. Cochrane Database Syst Rev. 2004:CD004293 Snyder S, Pendergraph B. Detection and evaluation of chronic kidney disease. Am Fam Physician. 2005;72:1723-32 Waldman M, Crew RJ, Valeri A, et al. Adult minimal-change disease: clinical characteristics, treatment, and outcomes. Clin J Am Soc Nephrol. 2007;2:445-53 Wu HM, Tang JL, Cao L, Sha ZH, Li Y. Interventions for preventing infection in nephrotic syndrome. Cochrane Database Syst Rev. 2010:CD003964 Yuan W, Wang J, Wu T. Chinese herbal medicine Huangqi type formulations for nephrotic syndrome. Cochrane Database Syst Rev. 2008:CD006335

Codes
ICD-9 code 581.9 Nephrotic syndrome with unspecified pathological lesion in kidney V13.03 Nephrotic syndrome

FAQ
What is the role of diuretic therapy in nephrotic syndrome?Diuretics may play a role, but they do not alter the natural history of the syndrome. Their use should be restricted to improving the patient's daily lifestyle to enable him or her to perform essential functions, such as nutritional intake, appropriate ambulation, and normal respiration. Minimal to moderate peripheral edema is not an urgent indication for diuretic use. Nephrotic patients are vulnerable to episodes of acute hypovolemia with acute kidney injury , and these are commonly precipitated by diuretics Is nephrotic syndrome a manifestation of the nephropathy associated with SLE ?Yes. Nephrotic syndrome is one type of lupus nephropathy (class V). A pure form of nephrotic syndrome in lupus is morphologically represented by the changes of membranous glomerulopathy on renal biopsy, with subepithelial deposits in the basement membrane. This is uncommon compared with lupus glomerulonephritis, which is typically manifested by a nephritic syndrome on urinalysis (proteinuria plus erythrocytes and erythrocyte casts). In addition, lupus membranous nephropathy may spontaneously change, as seen on biopsy and indicated by clinical manifestations, into a more common form of lupus glomerulonephritis

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What is an effective way to treat nephrotic syndrome associated with systemic diseases that appears on renal biopsy as FSGS ( eg , HIV-associated nephropathy , heroin-associated nephropathy, reflux nephropathy)?These forms of nephrotic syndrome do not respond to the conventional therapy such as corticosteroids or immunosuppressive therapy used to treat idiopathic nephrotic syndrome. The best approach is to provide supportive therapy, including control of the major risk factors for progression to end-stage disease (eg, hypertension ). ACE inhibitors or ARBs may control the degree of the proteinuria along with hypertension

Current contributors
Joseph Benjamin, MD , Professor of Clinical Medicine, Department of Medicine, Section of Nephrology and Kidney Transplantation, Temple University School of Medicine, Philadelphia, Pennsylvania, and Patricio Silva, MD , Section Chief, Nephrology and Kidney Transplantation, and Professor of Medicine, Department of Medicine, Section of Nephrology and Kidney Transplantation, Temple University School of Medicine, Philadelphia, Pennsylvania

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