Nephrotic Syndrome

Definition

• Manifestation of glomerular disease, characterized by nephrotic range proteinuria and a triad of clinical findings associated with large urinary losses of protein : hypoalbuminaemia , edema and hyperlipidemia

- Nelson Textbook of Paediatrics, Vol 2, 19th Edition, page 1801

Why ‘nephrotic range’

• Defined as – protein excretion of > 40 mg/m2/hr– Spot protein : creatinine ratio of > 3 : 1

– Hypoalbuminamia <2.5g/dl– Edema- generalised– S cholesterol 220mg/dl

- Nelson Textbook of Paediatrics, Vol 2, 19th Edition, page 1801

PathogenesisInherent susceptibility T CELL dysfuction

Release of lymphokines (IL 2)

Decrease in sialoprotein of glomerular basement membrane

Loss of net negative charge of glomerulusIncrease in pore size

Massive proteinuria

Loss of IgG Hypoalbuminamia Loss of AT-iii

Infections decrease in plasma oncotic pressure

Thrombotic episodes

hypoalbuminamia

fall in plasma oncotic pressure hypovolumia due to fluid leak from vressels

activation of Rennin Angiotension Aldosterone system

Retention of sodium and water odema

Also, hypoalbuminamia

Induces synthesis of Beta lipoprotiens from liver

Hyperlipidemia increased clotting factor synthesis

hyper coagulable state

Incidence ( paediatric ) ?

• 2 – 7 cases per 10,000 children per year• Higher in underdeveloped countries ( South

east Asia )• Occurs at all ages but is most prevalent in

children between the ages 1.5-6 years.• It affects more boys than girls, 2:1 ratio

http://www.kidney.org/site/107/pdf/NephroticSyndrome.pdf

Etiology

• Primary or idiopathic • Secondary

Primary or idiopathic

- Nelson Textbook of Paediatrics, Vol 2, 19th Edition, page 1804

Constitutes 90% of cases of childhood NS

Secondary causes• Congenital– TORCH Infections

• Infectious– Hepatitis (B,C) , HIV-1, Malaria, Syphilis, Toxoplasmosis

• Inflammatory– Glomerulonephritis

• Neoplastic– Lymphoma, Leukemia

• Drug induced – Penicillamine, Gold, NSAIDS, Pamidronate, Mercury,

Lithium

- Nelson Textbook of Paediatrics, Vol 2,19th edition, page 1802, table 521-1

Endocrine Diabetes MellitusMultisystem disorder SLE PAN Vasculitis due to any causeMiscellenious Insect bites Amyloidosis Sjogren syndrome

Histology classification

Minimal change NS NS With significant lesion 1 mesangioproliferative gn 2 FSGS 3 MPGN 4 Membranous nephropathy

Clinical Features

In children the commonest form of N.S. is

primary nephrotic syndrome • Among these the MCNS is the most frequent.

• Insidious onset of • odema• fever• oliguria

• Many children have recurrent episodes of such transient edema for many months.

• Physical examination shows•

• Edema – The edema is initially noted around the eyes and in the lower extremidies where it is pitting in nature, with time edema becomes generalized and may associate with weight gain and the development of ascites, pleural effusion and decreased urinal output. • Pallor • White nails with red bands (leukonychia) • Normal Blood Pressure• No evidence of Renal failure

NS WITH SIGNIFICANT LESIONS SUSPECTED IN FOLLOWING CONDITIONS

Age <1y or >8yHypertensionHaematuriaRenal dysfuctiuonExta renal symptomsRashArthrlagiaDecresed c3,c4

Complicatios of NS

A. Loss of Proteins:

Albumin Edema

Transferrin Anemia

TMG Biochemical hypothyroidism

Vit.D Binding Globulin Hypocalcemia (Along with loss1,25diOH chole calciferol)

Immunoglobulin Infection

Coagulation factors Hypercoagulable state

B. Infection:Loss of Immunoglobulin AcuteDepressed CMI Chronic

C. Hypercoagulable State: - due to alteration in coagulation factors, associated infections,

sepsis, Hypovolemiai) Renal Vein Thrombosisii) Peripheral Vein Thrombosisiii) Cerebral Vein Thrombosis

D. Renal Failure:

i) Chronic renal failure - as a part of disease process.

ii) Acute renal failurea) Hypovolemia induced ATNb) Septicemia leading to shock and ATNc) Septicemia causing bacterimia and AINd) Other drugs causing AINe) Bilateral renal vein thrombosis f) Crescentic GN on existing glomerular disease like FSGS,

MGN and MPGN.

E. Convulsions:

i) Hypocalcemia due to loss of Ca, 1, 25 di OH Cholecalciferol, Vit.D, binding protein in urine.

ii) Hypertensioniii) Renal failure – uraemiciv) Hyponatremiav) Cerebral Vein thrombosis

OTHERSPericardial effusion and hyrothorax d/t fluid retentionPostural hypotensionAtherosclerosis Loss of zn cu decrease in immunity

Hb %TCDCMxUrine ExaminationUrine Culture and Sensitivity X Ray ChestUSG AbdomenSerum Proteins Urinary Proteins Spot Urine Test Serum Cholesterol

Kidney Biopsy

Additional Tests• C3 and antistreptolysin O• Chest X ray and tuberculin test• ANA • Hepatitis B surface antigen

Ghai Essential Paediatrics,8th edition, page 478

Indications for Biopsy• Age below 12 months• Gross or persistent microscopic hematuria• Low blood C3• Hypertension• Impaired renal Function• Failure of steroid therapy

Therefore, presence of Proteinuria of 3+ or more Hyline cast on microscopyHypercholesterolemia> 220mg/ddlUrine spot protein creatinine ratio of >3oliguria

Is diagnostic of NS

Idiopathic Lab Findings

Minimal Change Nephrotic Syndrome Raised BUN in 15 – 30 %Highly Selective proteinuria

Focal Segmental Glomerulosclerosis Raised BUN in 20 – 40 %

MembranoproliferativeGlomerulonephritis

Type I Low C1, C4 , C3 – C9

Type II Normal C1, C4 , Low C3 – C9

- Nelson Textbook of Paediatrics, Vol 2 : page 1803, table 521-2

Cause Light microscopy

Immunoflorescence Electron Microscopy

Minimal Change Nephrotic Syndrome

Normal Negative Foot process fusion

Focal Segmental Glomerulosclerosis

Focal sclerotic lesions

IgM, C3 in lesions Foot process fusion

Membranous Nephropathy

Thickened GBM

Fine Granular IgG Sub epithelial deposits

MembranoproliferativeGlomerulonephritis

Type I Thickened GBM, proliferation

Granular IgG, C3 Mesangial and subendothelial deposits

Type II Lobulation C3 only Dense deposits

- Nelson Textbook of Paediatrics, Vol 2 : page 1803, table 521-2

Management

Initial Episode

Ghai Essential Paediatrics,8th edition, page 476, 477

Child is admitted in hospitalSalt restrictionTo decrease edemaTable salt contains 40% of Na and 60% of

chlorideSo normal salt is still advised only excess

consumption of salt is stopped

Fluid restrictionFluid intake is restricted to, insensible water loss

plus urine outputInsensible loss means lost through skin and

respiratory tractDiet Normal protien intake of 1.5-2g/kg/day is advised. .

Idli, idiyappam, rice puttu, sweet pongal, coconut rice, curd rice, lemon rice, beet-root, chappathi, dhall, sugar candy, boiled potato, carrot, cabbage, tomato and onion are accepted.

Control of edemaIt is an integral part ofsupportive care. Since treatment with

corticosteroids usually leads to diuresis within 5-10 days, diuretics are avoided unless edema is significant. Diuretics should also not be given to patients with diarrhea,.vomiting or hypovolemia.

Patients with persistent edema and weight gain of7-10% are treated with oral frusemide (1-3 mg/kgdaily). Additional treatment with potassium sparingdiuretics is not required if frusemide is used at thisdose for less than one week. Patients requiringhigher doses and prolonged duration of treatmentwith frusemide should receive potassium sparingdiuretics, e.g., spironolactone (2-4 mg/kg daily).Blood pressure should be monitored frequently. Agradual reduction of edema, over one week, ispreferred.

For patients with refractory edema, a combination of diuretics and albumin infusion is used. Albumin (20%) is given as an infusion at a dose of 0.5-1 g/kg over 2-4 hr, followed by administration of frusemide (1-2 mg/kg intravenously).

While infusion of albumin results in increased urine output, the effect is not sustained and repeated administration might be necessary,Albumin should be administered very cautiously in patients with renal failure, pneumonia or pulmonary edema due to its potential to increase the plasma volume. Patients receiving albumin should be observed for respiratory distress, hypertension and congestive heart failure

Examine for hypovolemia NoFrusemide 1-3 mg/kg/dayMay add spironolactone 2-4 mg/kg/day No response` (no weight loss or diuresis in 48 h) Double dose of frusemide until diuresis maximum daily

dose of frusemide(4-6 mg/kg/day) is reached No response Add hydrochlorthiazide 1-2 mg/kg/day or

metolazone 0.1-0.3 mg/kg/day No responseFrusemide IV bolus 1-3 mg/kg/dose infusion 0.1-1 mg/kg/h No response• 20% Albumin 1 g/kg IV• followed by IV frusemide

drugs to control proteinuria

• The standard medication for treatment is prednisolone or prednisone. The use of methylprednisolone,dexamethasone, betamethasone, triamcinoloneor hydrocortisone is not recommended. There is also limited evidence on the efficacy

or benefits of therapy with deflazocort for nephrotic syndrome.

first episode Prednisolone is administered at a dose of 2

mg/kg/day (maximum 60 mg in singleor divided doses) for 6 weeks, followed by

1.5mg/kg(maximum 40 mg) as a single morning dose on alternate days for the next 6 weeks; therapy is then discontinued.

Thus the duration of therapy in first episode is 12 weeks.

Remission Urine albumin nil or trace (or proteinuria <4 mg/m2/h) for 3 consecutive

early morning specimens.

Relapse Urine albumin 3+ or 4+ (or proteinuria >40 mg/m2/h) for 3 consecutive early

morning specimens,having been in remission previously.

Frequent relapses Two or more relapses in initial six months or more than three relapses in any

twelve months.

Steroid dependence Two consecutive relapses when on alternate day steroids or within 14 days

of its discontinuation.

Steroid resistance Absence of remission despite therapy with daily prednisolone at a dose of 2

mg/kg per day for 4 weeks

Treatment of RelapseThe patient should be examined for infections,which should be treated before initiating steroid

therapy.

Appropriate therapy of an infection might rarely result in spontaneous remission, there by avoiding the need for treatment with corticosteroids.

Prednisolone is administered at a dose of2 mg/kg/day (single or divided doses) until urineprotein is trace or nil for three consecutive days.

Subsequently, prednisolone is given in a singlemorning dose of 1.5 mg/kg on alternate days for4 weeks, and then discontinued. The usualduration of treatment for a relapse is thus 5-6

weeks.

In case the patient is not in remission despite two weeks treatment with daily prednisolone, the treatment is extended for 2 more weeks. Patients showing no remission despite 4 weeks’ treatment with daily prednisolone should be treated as steroid resistance.

Infrequent Relapsers• Patients who have three or less relapses a year

and respond promptly to prednisolone are managed using the aforementioned regimen for each relapse.Such children are at a low risk for developing steroid toxicity.

Frequent Relapsers and Steroid DependencePatients with frequent relapses or steroid

dependence should be managed in consultation with a pediatric nephrologist.

It is usually not necessary to perform a renal biopsy in these cases. Following treatment of a relapse, prednisolone is gradually tapered to maintain the patient in remission on alternate day dose of 0.5-0.7 mg/kg, which is administered for 9-18 months.

A close monitoring of growth and bloodpressure, and evaluation for features of steroidtoxicity is essential. If the prednisolone threshold,to maintain

remission, is higher or if features of corticosteroid toxicity are seen, additional use of the following immuno-modulators is suggested.

• (a) Levamisole is administered at a dose of2-2.5 mg/kg on alternate days for 12-24months. Co-treatment with prednisolone at a dose of 1.5 mg/kg on alternate days is given for 2-4 weeks; its dose is gradually reduced by 0.15-0.25 mg/kg every 4 weeks to a maintenance dose of 0.25-0.5 mg/kg that is continued for six or more months.

The chief side effect of levamisole are leukopenia; flu-like symptoms,liver toxicity, convulsions and skin rash . The leukocyte count should be monitoredevery 12-16 weeks.

• b) Cyclophosphamide is administered at adose of 2-2.5 mg/kg/day for

12 weeks.Prednisolone is co-administered at a dose of1.5 mg/kg on alternate days for 4 weeks,followed by 1 mg/kg for the next 8 weeks;steroid therapy is tapered and stopped over thenext 2-3 months. Therapy with cyclophosphamide should be instituted preferablyfollowing remission of proteinuria.

Total leukocyte counts are monitored every2 weeks; treatment with cyclophosphamide istemporarily discontinued if the count fallsbelow 4000/mm3. An increased oral fluidintake

and frequent voiding prevents the complication of hemorrhagic cystitis; otherside effects are alopecia, nausea and vomiting.The risk of gonadal toxicity is limited with a single (12 weeks) course of cyclophosphamide. The use of more than one course of this agent should preferably be avoided.

(c) Calcineurin inhibitors: Cyclosporin (CsA) isgiven at a dose of 4-5 mg/kg daily for 12-24months. Prednisolone is co-administered at adose of 1.5 mg/kg on alternate days for 2-4weeks; its dose is gradually reduced by 0.15-0.25 mg/kg every 4 weeks to a maintenancedose of 0.25-0.5 mg/kg that is continued for sixor more months. Occasionally, treatment

withcorticosteroids may be discontinued

Side effects of CsA therapy include, hypertension, cosmetic symptoms(gum

hypertrophy, hirsutism) and nephrotoxicity;hypercholesterolemia and elevated transaminases may occur. Estimation of blood levels of creatinine is required every 2-3months and a lipid profile annually. A repeat kidney biopsy, to examine for histologicalevidence of nephrotoxicity, should be done iftherapy with calcineurin inhibitors is extendedbeyond 2 years.

Tacrolimus is an alternative agent, administeredat a dose of 0.1-0.2 mg/kg daily for 12-24months.

Side effects include hyperglycemia,diarrhea and rarely neurotoxicity (headache,seizures). The use of tacrolimus is preferred especially in adolescents, because of lack of

cosmetic side effects . Blood levels of creatinine and glucose should be estimated every 2-3 months.

(d) Mycophenolate mofetil (MMF)is given at dose of 800-1200 mg/m2 along with tapering

doses of prednisolone for 12-24 month.The

principal side effects include gastrointestinaldiscomfort, diarrhea and leukopenia.Leukocyte counts should be monitored every1-2 months; treatment is withheld if count fallsbelow 4000/mm3.

Patient and parent educationParental motivation and involvement is essentialin the long-term management of these children.

They should be provided information about the disease, its expected course and risk of complications. The following are emphasized

(a) Urine examination for protein at home usingdipstick, sulfosalicylic acid or boiling test. Theexamination should be done every morningduring a relapse, during intercurrent infectionsor if there is even mild periorbital puffiness.

(b) Maintain a diary showing results of urineprotein examination, medications received andintercurrent infections.(c) Ensure normal activity and school

attendance;the child should continue to participate in allactivities and sports.

(d) Since infections are an important cause ofmorbidity, patients should receive appropriateimmunization and other measures for protection

Immunization: Parents should be advised regardingthe need for completing the primary

immunization.Administration of some vaccines, e.g., hepatitis B,measles-mumps-rubella or meningococcal vaccinesmay rarely precipitate a relapse.

Patients receiving prednisolone at a dose of 2 mg/kg/day or greater, or total 20 mg/day or greater (forpatients weighing >10 kg) for more than 14 days areconsidered immunocompromised. Such patientsshould not receive live attenuated vaccines;inactivated or killed vaccines are safe).

Live vaccines are administered once the child is off immunosuppressive medications for at least 4weeks. If there is a pressing need, these vaccines maybe given to patients receiving alternate day prednisolone at a dose less than 0.5 mg/kg.

All children with nephrotic syndrome shouldreceive immunization against pneumococcal and

chickenpox infections.

Complications of steroid treatmentPatients with steroid sensitive nephrotic

syndrome are at risk for certain complications, early detection of which is necessary.

InfectionsPeritonitis Children with nephrotic syndrome aresusceptible to severe infections, which need

prompttreatment. Common infections include peritonitis,cellulitis and pneumonia.

Thrombosis: Children with nephrotic syndromeare at risk for venous and, rarely, arterialThrombosis. Patients with thrombotic

complications require urgent treatment. The treatment includes correction of

dehydration and other complications, and use of heparin (IV) or low-molecular-weight heparin (subcutaneously) initially, followed by oral anti-coagulants on the long-term

Hypertension: This may be detected at the onset ofnephrotic syndrome or later due to steroid

toxicity.Therapy is initiated with ACE inhibitors, calciumchannel blockers or β adrenergic antagonists,keeping the blood pressure at less than the 90thpercentile.

All patients should be monitored forcushingoid features and blood pressure; six-

monthly record of height and weight, and yearly evaluation for cataract should be done. Patients on prolonged (>3 months) treatment with steroids should receivedaily supplements of oral calcium (250-500 mgdaily) and vitamin D (125-250 IU

INDICATIONS FOR REFERRAL TO A PEDIATRICNEPHROLOGIST• Onset below 1-year of age; • family history of nephroticsyndrome.• Nephrotic syndrome with hypertension, gross/persistent

microscopic hematuria, impaired renal function, or extrarenal features (e.g., arthritis, serositis, rash).

• Complications: refractory edema, thrombosis, severeinfections, steroid toxicity.• Resistance to steroid therapy. Frequently relapsing or steroid dependent nephrotic

syndrome

Prognosis85%cases NS respond to steroids.5% cases recover spontaneously.10%cases are steroid dependent.

In cases with significant lesions 1/3rd recover spontaneouslyAnother 1/3rd cases go for CRF.