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Overview of Overview of Nephrotic Nephrotic

Syndrome (NS)Syndrome (NS)BY CJ LauBY CJ Lau

3 June 20093 June 2009

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BackgroundBackground Is not a disease but a collection of Is not a disease but a collection of

symptomssymptoms Not be to confused with nephritic Not be to confused with nephritic

syndromesyndrome Also known as nephrosisAlso known as nephrosis Characterized by :Characterized by :1.1. ProteinuriaProteinuria2.2. HypoalbuminemiaHypoalbuminemia3.3. HyperlipidemiaHyperlipidemia4.4. edemaedema

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Nephrotic syndrome

(gromerular diseases intrinsic to the kidney)

Classification

Primary/idiopathic NS

-Minimal change nephrotic syndrome (MCNS)-Focal segmental glomerulosclerosis (FSGS)-Membranous nephropathy (MN)

Secondary(etiology extrinsic to the kidney)

-Hepatitis B & C-Diabetes mellitus-Syphilis-Systemic Lupus Erythematous-drug exposure (eg. lithium & mercury)

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PathophysiologyPathophysiology

proteinuria- concentration of heparan proteinuria- concentration of heparan sulfate(-ve charged) in the basement sulfate(-ve charged) in the basement membrane is lower in NS patients, filtration membrane is lower in NS patients, filtration of plasma protein(-ve charged) through of plasma protein(-ve charged) through glomerular membrane is prevented by a glomerular membrane is prevented by a negatively charged filtration barriersnegatively charged filtration barriers

Hypoalbuminemia-glomerular capillary Hypoalbuminemia-glomerular capillary permeability to albumin is selectively permeability to albumin is selectively increased, leads to hyperalbuminurea and increased, leads to hyperalbuminurea and eventually hypoalbuminemia eventually hypoalbuminemia

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PathophysiologyPathophysiology

Edema- hypoalbuminemia lowers the Edema- hypoalbuminemia lowers the plasma colloid osmotic pressure, plasma colloid osmotic pressure, causing transcapillary filtration of causing transcapillary filtration of water and the development of edemawater and the development of edema

Hyperlipidemia- hypoproteinemia Hyperlipidemia- hypoproteinemia stimulates generalized protein stimulates generalized protein synthesis in liver including synthesis in liver including lipoprotein.lipoprotein.

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EpidemiologyEpidemiology

99thth leading cause of death in Sarawak leading cause of death in Sarawak general hospital in 2006 (3.41% of total general hospital in 2006 (3.41% of total death)death)

Children at any age and adults can get it, Children at any age and adults can get it, but usually children between the age of 1 but usually children between the age of 1 ½ -4 are more prone½ -4 are more prone

Boys are twice more susceptible than Boys are twice more susceptible than girlsgirls

In adults, male-female prevalence is In adults, male-female prevalence is approximately equalapproximately equal

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Clinical PresentationClinical Presentation

Increasing edema over a few days or Increasing edema over a few days or weeks, lethargy, poor appetite and weeks, lethargy, poor appetite and occasional abdominal painoccasional abdominal pain

Edema is the predominant feature, Edema is the predominant feature, initially develops around eyes & lower initially develops around eyes & lower extremities, becomes generalized and extremities, becomes generalized and leads to weight gainleads to weight gain

Decline in urine output and frothy urineDecline in urine output and frothy urine Hematuria and hypertension are unusualHematuria and hypertension are unusual

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DiagnosisDiagnosis First morning urine protein/creatinine value First morning urine protein/creatinine value

greater than 2-3mg/mg or 24hours urine greater than 2-3mg/mg or 24hours urine protein level of more than 40mg/mprotein level of more than 40mg/m22/hr/hr

Serum albumin level less than 2.5g/dL Serum albumin level less than 2.5g/dL (normal 3.5-5g/dL)(normal 3.5-5g/dL)

Elevated total cholesterol, low density Elevated total cholesterol, low density lipoprotein (LDL) and triglycerides.lipoprotein (LDL) and triglycerides.

Normal or low high density lipoprotein Normal or low high density lipoprotein (HDL).(HDL).

Check creatinin and urea level to evaluate Check creatinin and urea level to evaluate renal functionrenal function

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TreatmentTreatment Renal biopsy – not indicated for INS in Renal biopsy – not indicated for INS in

children prior to starting corticosteroid children prior to starting corticosteroid therapy. It is indicated for steroid resistant therapy. It is indicated for steroid resistant NS (not achieving remission despite NS (not achieving remission despite 4weeks of adequate corticosteroid 4weeks of adequate corticosteroid therapy). Other indication would depends therapy). Other indication would depends on presence of features to suggest other on presence of features to suggest other renal diseases such as persistent renal diseases such as persistent hypertension and haematuria. Decision is hypertension and haematuria. Decision is up to attending pediatrician in up to attending pediatrician in consultation with the pediatric consultation with the pediatric nephrologists.nephrologists.

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Management of edematous Management of edematous statestate

Antibiotics- penicillin V 125mg BD (1-5years Antibiotics- penicillin V 125mg BD (1-5years old),250mg BD (6-12years old) and 500mg old),250mg BD (6-12years old) and 500mg BD (>12years old) is recommended during BD (>12years old) is recommended during relapse particularly with gross edema.relapse particularly with gross edema.

Diet-A normal protein diet with adequate Diet-A normal protein diet with adequate calories is recommended. No added salt to calories is recommended. No added salt to the diet during the edematous state.the diet during the edematous state.

Fluid restriction- Not usually recommended Fluid restriction- Not usually recommended except in chronic edematous state.except in chronic edematous state.

Diuretics- Frusemide is usually not Diuretics- Frusemide is usually not necessary in steroid responsive NS but if necessary in steroid responsive NS but if require should be used with caution as it can require should be used with caution as it can precipitate hypovolaemia.precipitate hypovolaemia.

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Management of edematous Management of edematous statestate

Human albumin (20-25%) at 0.5-1.0g/kg can Human albumin (20-25%) at 0.5-1.0g/kg can be used in symptomatic edematous state be used in symptomatic edematous state together with IV frusemide at 1-2mg/kg to together with IV frusemide at 1-2mg/kg to produce a diuresis. Urine output and blood produce a diuresis. Urine output and blood pressure should be closely monitored.pressure should be closely monitored.

Human albumin at 0.5-1.0g/kg of 5%, 20% Human albumin at 0.5-1.0g/kg of 5%, 20% or 25% (whichever is available) over one or 25% (whichever is available) over one hour should be given in those suspected to hour should be given in those suspected to have hypovolaemia. Do not give frusemide have hypovolaemia. Do not give frusemide in this instant.in this instant.

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CorticosteroidsCorticosteroids Effective in inducing remission of NSEffective in inducing remission of NS Prednisolone dosage orally for children- Prednisolone dosage orally for children-

60mg/m60mg/m22/day or 2mg/kg/day in divided dose /day or 2mg/kg/day in divided dose 3-4times (maximum of 80mg/day) for 4 3-4times (maximum of 80mg/day) for 4 weeks. Followed by 40mg/mweeks. Followed by 40mg/m22/dose or 1-/dose or 1-1.5mgmg/kg/alternate day for 4weeks. 1.5mgmg/kg/alternate day for 4weeks. Reduce prednisolone dose by 25% monthly Reduce prednisolone dose by 25% monthly over next 4months.over next 4months.

Monitor blood pressure, blood glucose.Monitor blood pressure, blood glucose. 95% of children will achieve remission 95% of children will achieve remission

defined as urine dipstick in trace or nil for 3 defined as urine dipstick in trace or nil for 3 consecutive days within 28days . consecutive days within 28days .

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Treatment of relapseTreatment of relapse Relapse is defined by urine albumin Relapse is defined by urine albumin

excretion more than 40mg/mexcretion more than 40mg/m22/hour, dipstick /hour, dipstick of 2+ or more for 3 consecutive days.of 2+ or more for 3 consecutive days.

Prednisolone 60mg/mPrednisolone 60mg/m22/day until remission /day until remission then 40mg/mthen 40mg/m22/dose for 4 weeks and off./dose for 4 weeks and off.

Frequent relapse -2 or more relapses within Frequent relapse -2 or more relapses within 6 months of initial response.6 months of initial response.

Treatment-Prednisolone 60mg/mTreatment-Prednisolone 60mg/m22/day till nil /day till nil albumin in urine for 3 days then albumin in urine for 3 days then 40mg/m40mg/m22/alternate mornings for 4weeks. /alternate mornings for 4weeks. Taper prednisolone dose every 2weeks and Taper prednisolone dose every 2weeks and keep on as low alternate day dose as keep on as low alternate day dose as possible for 6 months. possible for 6 months.

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Management of steroid Management of steroid dependentdependent

Defined as 2 consecutive relapses Defined as 2 consecutive relapses ocurring during the period of steroid ocurring during the period of steroid taper or 14 days of its cessation.taper or 14 days of its cessation.

If a child is not steroid toxic If a child is not steroid toxic (eg.cushing syndrome), reinduce (eg.cushing syndrome), reinduce with steroids and maintain on as low with steroids and maintain on as low dose of alternate day prednisolone dose of alternate day prednisolone as possible as possible.as possible as possible.

If child is steroid toxic, consider If child is steroid toxic, consider cyclophosphomide therapy.cyclophosphomide therapy.

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Steroid resistant NSSteroid resistant NS

Refer for renal biopsy- specific Refer for renal biopsy- specific treatment will depend on the treatment will depend on the histopathology.histopathology.

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CyclophosphamideCyclophosphamide An alkylating agent, also possess potent An alkylating agent, also possess potent

immunosuppressive activity.immunosuppressive activity. Indicated for the treatment of steroid dependent Indicated for the treatment of steroid dependent

nephrotic syndrome with sigh of steroid toxicity.nephrotic syndrome with sigh of steroid toxicity. Dose- Oral: 2-3mg/kg/day everyday for up to Dose- Oral: 2-3mg/kg/day everyday for up to

12weeks12weeks Monitoring parameters- Complete blood count Monitoring parameters- Complete blood count

with blood count, serum creatininewith blood count, serum creatinine Adverse effects-hemorrhagic cystitis (drink plenty Adverse effects-hemorrhagic cystitis (drink plenty

of fluids, avoid taking drug at night), leucopeniaof fluids, avoid taking drug at night), leucopenia

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Complication of NSComplication of NS Infection - due to low IgG level and impaired T-cell functions in Infection - due to low IgG level and impaired T-cell functions in

INS patients. Medications used to treat NS (corticosteroids) INS patients. Medications used to treat NS (corticosteroids) further suppress immune system. Patients are at risk of further suppress immune system. Patients are at risk of infection, especially with Streptococcus Pneumonia. Patients infection, especially with Streptococcus Pneumonia. Patients infected with varicella should be treated with acyclovir.infected with varicella should be treated with acyclovir.

Thromboembolism- renal vein thrombosis, deep vein Thromboembolism- renal vein thrombosis, deep vein thrombosis, and pulmonary thrombosis are common due to thrombosis, and pulmonary thrombosis are common due to increase platelet activation and aggregation, decreased increase platelet activation and aggregation, decreased antithrombin III, protein C & S which leads to hypercoagulable antithrombin III, protein C & S which leads to hypercoagulable state in INS. Following tromboembolism, warfarin is often state in INS. Following tromboembolism, warfarin is often prescribed for a period of 6 months. Some practitioners prescribed for a period of 6 months. Some practitioners advocate the use of low dose aspirin in chronic NS patients, advocate the use of low dose aspirin in chronic NS patients, however, adequate clinical trials examining the use of aspirin however, adequate clinical trials examining the use of aspirin have not been performed.have not been performed.

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Patient educationPatient education

Home monitoring of first morning urine Home monitoring of first morning urine protein with urine dipstickprotein with urine dipstick

Weight should be checked and a home logbook Weight should be checked and a home logbook should be kept (include the steroid dose taken)should be kept (include the steroid dose taken)

Consult doctor if edema, weight gain, or Consult doctor if edema, weight gain, or proteinurea persist for more than 2daysproteinurea persist for more than 2days

Control fluid (urine volume+500ml) and salt Control fluid (urine volume+500ml) and salt intakeintake

Yearly influenza vaccination and Yearly influenza vaccination and pneumococcal vaccination (every 5years) are pneumococcal vaccination (every 5years) are recommended.recommended.

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ReferencesReferences http://emedicine.medscape.com/article/982920-overviewhttp://emedicine.medscape.com/article/982920-overview http://www.myhealth.gov.my/myhealth/bm/dewasa_content.jsp?http://www.myhealth.gov.my/myhealth/bm/dewasa_content.jsp?

lang=dewasa&sub=0&bhs=may&storyid=1161239049200lang=dewasa&sub=0&bhs=may&storyid=1161239049200 http://www.kidney.org/Atoz/atozItem.cfm?id=53 (national kidney http://www.kidney.org/Atoz/atozItem.cfm?id=53 (national kidney

foudation)foudation) http://www.hkl.gov.my/content/hfacts/death2007.htmhttp://www.hkl.gov.my/content/hfacts/death2007.htm Drug information Handbook, Lexi-CompDrug information Handbook, Lexi-Comp http://mpaeds.org.my/PaediatricProtocols/46.%20Nephrotichttp://mpaeds.org.my/PaediatricProtocols/46.%20Nephrotic

%20Syndrome.pdf%20Syndrome.pdf Consensus of statement – Management of idiopathic nephrotic Consensus of statement – Management of idiopathic nephrotic

syndrome in childhood. Ministry of Health. Academy of Medicine syndrome in childhood. Ministry of Health. Academy of Medicine Malaysia 1999.Malaysia 1999.

Hodson EM, Knight JF, Willis NS, Craig JC. Corticosteroid therapy for Hodson EM, Knight JF, Willis NS, Craig JC. Corticosteroid therapy for nephrotic syndrome in children. The Cochrane library, Issue nephrotic syndrome in children. The Cochrane library, Issue 1,2003.Oxford1,2003.Oxford

Durkan A, Hodson E, Willis N, Craig J. Non corticosteroid treatment Durkan A, Hodson E, Willis N, Craig J. Non corticosteroid treatment for nephrotic syndrome in children. The Cochrane library, Issue 1, for nephrotic syndrome in children. The Cochrane library, Issue 1, 2003, Oxford.2003, Oxford.