NEPHROTIC SYNDROME

Introduction

Develops when an abnormality of glomerular permeability results in heavy proteinuria (>3.5g/24hr), hypoalbuminaemia (<30g/L) & generalized edema Childhood majority is 1 glomerular disorder 80% of cases of childhood NS are attributable to minimal change disease (MCNS)

Cont

Minimal changes disease (MCNS)

Male > female (3:2) Most cases, onset between ages 2-6 years with median age at presentation of 3 years Etiology remain incompletely defined There appears to be an abnormality of the negatively charged residues in the glomerular basement membrane, which normally limit the filtration of anion plasma protein (e.g. albumin) Typically responds to corticosteroids therapy & usually associated with a favourable long-term outcome At least 70% of patient will experience a chronic, relapsing-remitting course

Cont

Heterogeneous group of conditions, including focal segment glomerulosclerosis (FSGS) & mesangiocapillary glomerulonephritis (MCGN) account for remaining 20% of cases of NS in childhood

Compared to MCNS, these disease tend to present in older children Majority of patient do not enter remission with standard initial corticosteroid therapy Their prognosis is correspondingly poorer

Cont
Majority of cases respond to empirical corticosteroid therapy without the underlying histological diagnosis being confirmed Steroid sensitive nephrotic syndrome (SSNS) was adopted for this group

Cont
Histological diagnosis in children presenting with NS & outcome of corticosteroid therapy
Nephrotic children 100 Minimal change 80 Steroid sensitive 75 Steroid resistant 5 FSGS 10 Steroid sensitive 2 Steroid resistant 8 MCGN & Others 10 Steroid sensitive 2 Steroid resistant 8

Clinical features & diagnosis

Recognition of illness & the formulation of a diagnosis Usual presenting symptom is edema important to exclude other condition Edema initially present in a peri-orbital distribution, which particularly noticeable in the morning after the child has been recumbent overnight

Differential diagnosis of generalized edema

Renal condition
Nephrotic syndrome Acute nephritic syndrome Acute renal failure

Non-renal condition
Severe cardiac failure Chronic liver disease Protein-losing enteropathy

As further ECF accumulates edema develops in the dependent areas of lower limb & genitals In more advanced cases, fluid accumulation in the serous body cavities pleural effusion & ascites Onset of illness is often preceded by a history of viral URTI & the development of edema may be accompanied by general malaise & irritability

Clinical assessment of NS
History of presenting illness

Age Duration & progress of symptoms Fluid intake Urine output

Adequate/oliguric Often viral URTI in SSNS

Antecedent illness

Past medical history

History of atopic disease

Present in 30-60% of cases of SSNS Risk of severe infection in non-immune patients after immunosuppression

Previous vericella infection

Cont
Drug history

Including immunization history

Family history

History of NS

~3% of NS patient have an affected sibling: histological type & steroid responsiveness are usually similar within family May suggest poor prognosis if CRF was preceded by SRNS

Chronic renal failure

Cont

Examination
Height & weight BP Pulse capillary refill time Plural effusion Ascites edema

Cont
Acute complication

Hypovolaemia Infection Thrombosis

Age <1 year or >12 years Persistent hypertension Gross haematuria Renal impairment Plasma C3

Chronic complication

1st line investigation in NS

Patients presenting with typical features of uncomplicated NS require only limited initial investigation

Urine dipstick analysis (protein, blood) Early morning urine protein/creatinine ratio Urine microscopy and culture Plasma albumin, creatinine and electrolytes FBC Complement C3 & C4 levels Varicella zoster antibody titres Hepatitis serology (Type B & C)

Atypical features

Considered in SSNS & suggest the possibility of an alternative diagnosis (which is less likely to respond to corticosteroid therapy) Principal atypical features

Age <1 year or >12 years Persistent hypertension Persistent renal impairment Gross haematuria Low plasma C3 concentration

2nd line investigation in NS

Atypical features warrant further investigation & should be referred to a paediatric nephrologists
Antistreptolysin O titre (ASOT) Antinuclear antibodies (ANA) Anti-ds DNA antibodies

General management
General management
Fluid balance Prophylaxis

Blood pressure monitoring

Mobilization & Diet

Information for parents

Fluid balance

Salt-restricted diet Daily weight measurement If no hypovolaemia: -Advise for modestly restricted fluid intake -Diuretics e.g frusemide 2mg/kg per 24h may be combined with spironolactone 2mg/kg per 24h

Blood pressure monitoring

Children with MCNS/SSNS usually normotensive Hypotension-sign of hypovolaemia Hypertension requires careful evaluation If necessary, oral nifedipine(200g/kg per dose 3 times a day) may be used as an initial antihypertensive treatment.

Prophylactic antibiotics

Other than albumin, other important plasma proteins are lost in urine of nephrotic children. Urinary loss of immunoglobulins and complement components leads to susceptibility to bacterial infection.

e.g peritonitis (Streptococcus pneumoniae) septicemia (streptococci and Gram-negative organism) cellulitis (staphylococci)

Commonly, prophylactic antibiotics prescribed (oral phenoxymethylpenicillin 12.5mg/kg per dose twice daily)

Mobilization and Diet

Mobilization To prevent venous thrombosis Encourage patient to mobilize as normal and avoid bed rest. Diet No specific dietary advice Salt restriction Healthy eating

Information for parents

Explain the diagnosis Management plan Importance of compliance with medication Adverse effect of medication Need of outpatient follow-up

* In patient hospitalized in the first nephrotic episodes,

educate parents how to perform dipstick test to enable monitoring for relapse after discharge

Approach to an adult patient with Nephrotic Syndrome

1.Confirm diagnosis 2.Search for 2 causes/1 renal disease i. thorough history and physical examination ii. further laboratory investigations iii. renal biopsy 3.Assessment of i. renal function ii. complications 4.Management i. render patient asymptomatic (relief of edema) ii. treat underlying cause iii. maintain normal renal function iv. treat complications

Cont
i. Relief of edema
-low salt diet(50-100mmol sodium/day) -normal protein intake -Diuretics-oral or iv

ii. Treat underlying cause

1 renal disease-steroid -cytotoxics eg.cyclophosphamide 2 causes-eg treat diabetes mellitus, Hep B carrier, myeloma

Cont
iii. Treat complications of Nephrotic Syndrome
-succeptibility to infection -thrombosis -hyperlipidaemia -loss of binding proteins in urine -protein malnutrition -acute renal failure

Specific management
1.

For initial episode of NS

Prednisolone 60 mg/m, 3x daily followed by prednisolone 40 mg/m on alternate days for 14 doses over 28 days

Cont
2.

For relapsing episode

prednisolone 60 mg/m2, 3x daily until remission followed by prednisolone 40 mg/m on alternate days for 14 doses over 28 days only use for the first 2 relapses about 25% of relapses remit spontaneously, but need to be treated after 35 days to:

minimize steroid use avoid hypoalbuminaemia allow possibility of spontaneous remission

Standard definitions in monitoring of SSNS

Remission urine protein dipstick (Albustix) reading 0 or trace for 3 consecutive days Relapse Albustix reading 2+ or more for 3 consecutive days, having previously been in remission Frequently relapsing NS 2 relapses within 6 months of initial response or 4 relapses within any 12 months period Steroid dependant NS 2 consecutive relapses occurring during corticosteroid treatment or within 14 days after its cessation

Cont
3.

For frequent relapse

maintenance prednisolone: 0.1-0.5 mg/kg on alternate days up to 12 months

4.

If patient develops frequent relapses with steroid dependency: refer to a nephrologist

Side effect of prednisolone (corticosteroid)

Susceptibility to infection Mood & behavioural disturbance Increase appetite Weight gain & obesity Cushingoid appearance Acne Hirsutism Cutaneous striae Posterior subcapsular cataracts

Hypertension Growth suppression Pubertal delay Adrenal suppression Impaired glucose metabolism Dyspepsia & peptic ulceration Acute pancreatitis Osteoporosis Avascular osteonecrosis

Subsequent management
For patient on maintenance prednisolone
Follow-up every 3 months to check BP & growth (pubertal status, bone age graft) Cataract assessment annually A steroid warning card should be given

Alternative immunomodulatory therapy for NS

Indication for alternative immunomodulatory therapy in steroid-sensitivity NS

Relapse while taking prednisolone >1 mg/kg on alternate days Relapse while taking prednisolone >0.5 mg/kg on alternate days + 1 of the following

Unacceptable adverse effect of corticosteroid therapy High risk of adverse steroid effects (e.g. boys approaching puberty, diabetic children) Unusually severe relapses (hypovolaemia, thrombosis, severe sepsis, acute renal failure

Immunomodulatory therapy
1. Levamisole
Use after remission with prednisolone: 2.5 mg/kg on alternate days Then tapering & discontinue MOA: not fully understood Advantage

Safe Very infrequently case neutropaenia

Cont
2. Alkylating agents

Cyclophosphamide: use after remission with prednisolone 3 mg/kg daily dose for 8 weeks course Advantage:

induce long term remission/reduction of relapse frequency Bone marrow suppression Risk of infection Gonadal toxicity for male patient

Disadvantage:

Cont
3. Cyclosporin

To control frequent relapse recurring after previous course of cyclophosphamide. OR Pt. at high risk of cyclophosphamide side effect (e.g. peripubertal boys) Give after remission with prednisolone: 2.5 mg/kg per dose twice a day then discontinue when achieve therapeutic level Disadvantage

Only effective in maintaining remission during period of administration. (dyscontinue relapse) Chronic nephrotoxicity: renal biopsy should be done after 18-24 months of therapy Tremor Hypertrichosis Gingival hypertrophy hypertension

Long-term prognosis

In childhood very good 20% of pediatric patient: will have relapses on teenage years 5 years remission 20% of patient of relapse subsequently After 10 years remission, risk of relapse decrease Mortality rate 1-7.2% (mostly in 1960-1970) largely d/t acute complication of sepsis & vascular thrombosis

Diagnosis Nephrotic syndrome is a clinical syndrome of massive proteinuria defined by 1. Oedema 2. Hypoalbuminaemia of < 25g/l 3. Proteinuria > 40 mg/m2/hour ( > 1g/m2/day ) OR an early morning urine protein creatinine index of > 200 mg/mmol ( > 3.5 mg/mg ) 4. Hypercholesterolaemia is not needed in definition The main cause of nephrotic syndrome in children is primary or otherwise known as idiopathic nephrotic syndrome when the actual cause of the nephrotic syndrome is unknown. The treatment for nephrotic syndrome caused by other diseases example post streptococcal glomerulonephritis or systemic lupus erythematosus follows that for the treatment of the primary renal/systemic disorder.

Investigations at initial presentation 1. Full blood count 2. Renal profile - urea, electrolyte, creatinine 3. Serum albumin 4. Urinalysis and Culture 5. Quantification for urinary protein excretion (spot urine protein creatinine ratio or 24 hour urine protein) Other investigations if the clinical features are atypical / presence of poor prognostic features 1. Antinuclear factor / anti ds DNA 2. Serum complement (C3, C4) level 3. ASOT 4. Others as indicated

Renal biopsy Not indicated for idiopathic nephrotic syndrome in children prior to starting corticosteroid therapy. Main indication is steroid resistant nephrotic syndrome defined as failure to achieve remission despite 4 weeks of adequate corticosteroid therapy. Other indications would depend on presence of atypical features and features to suggest other renal diseases e.g. persistent hypertension, gross haematuria and shall be left to the discretion of the attending paediatrician in consultation with the paediatric nephrologist.

Management A. Management of the oedematous state Bed rest This is not required and usually not practical unless the child has gross oedema. Diet A normal protein diet with adequate calories is recommended. No added salt to the diet during the oedematous state. Antibiotics. Penicillin V 125 mg BD (1-5 years old); 250 mg BD (6-12 years old) 500 mg BD (>12 years) is recommended during relapse particularly with gross oedema.

o Human albumin (20-25%) at 0.5 1.0 g/kg can be used in symptomatic grossly oedematous states together with intravenous frusemide at 1-2 mg/kg to produce a diuresis. Caution: fluid overload and pulmonary oedema with salt poor albumin infusion. Urine output and blood pressure should be closely monitored. o Human albumin at 0.5 1.0 g/kg of 5%, 20% or 25% (whichever is available) over one hour in those suspected to have hypovolaemia/underfilled state. Do not give frusemide in this instant

Fluid status Carefully assess the haemodynamic status. Check for signs and symptoms which may indicate underfilling abdominal pain, cold peripheries, tachycardia and poor pulse volume, low blood pressure or overfilling e.g. basal lung crepitations and rhonchi, hypertension. Fluid restriction - not usually recommended except in chronic oedematous states. o Diuretics. e.g. frusemide is not usually necessary in steroid responsive nephrotic syndrome but if required should be used with caution as it can precipitate hypovolaemia.

B. Management of the complications of nephrotic syndrome Hypovolaemia. Clinical features: abdominal pain, cold peripheries, poor pulse volume, hypotension, and haemoconcentration. Treatment: infuse salt poor albumin at 0.5 to 1.0 g/kg/dose over one hour. If salt poor albumin is not available, other volume expanders like 5% albumin, plasma protein derivatives or human plasma can be used. Primary Peritonitis Clinical features: fever, abdominal pain in children with frank nephrotic syndrome. Investigations: Blood culture, peritoneal fluid culture (not usually done) Treatment: parenteral penicillin and a third generation cephalosporin Thrombosis Thorough investigation and adequate treatment with anticoagulation is usually needed.

C. General advice Inform regarding high probability (85-95%) of relapse. Home urine albumin monitoring. Urine dipstix testing of the first urine specimen in the morning daily. Parents are advised to consult the doctor if albuminuria > 2+ for 3 consecutive days. Immunocompromised status

o The parents and children should be advised and cautioned about contact with chickenpox and measles, and if exposed should be treated like any immunocompromised child. Immunisation. While the child is on corticosteroid treatment and within 6 weeks after its cessation, only killed vaccines may safely be administered to the child. Live vaccines can be administered 6 weeks after cessation of corticosteroid therapy.

Acute Adrenal Crisis This may be seen in children who have been on long term corticosteroid therapy (equivalent to 18 mg/m2 of cortisone daily) when they undergo situations of stress. Prevention and treatment: corticosteroids (hydrocortisone) given in 3 divided doses at 2-4 mg/kg/dose.

D. Corticosteroids Corticosteroids is effective in inducing remission of nephrotic syndrome but the most optimal dose and duration is yet to be resolved although it has been found that longer duration results in more prolonged remission. Prednisolone dosage at: * 60 mg / m2 / day ( maximum 80 mg / day ) for 4 weeks * followed by 40 mg / m2 / EOD (maximum 60 mg) for 4 weeks. * then reduce prednisolone dose by 25% monthly over next 4 months. 90% of children will achieve remission defined as urine dipstix is trace or nil for 3 consecutive day within 28 days, many within 7 - 14 days. Steroid resistance is defined as failure to achieve response to an initial 4 weeks treatment with prednisolone 60 mg/m2/day and such case should be referred to a nephrologist for a renal biopsy.

Treatment of relapses The majority of children with nephrotic syndrome will relapse. A relapse is defined by urine albumin excretion > 40 mg / m2 / hour or urine dipstix of 2+ or more for 3 consecutive days. Treatment - Prednisolone 60 mg/m2 /day until remission then 40 mg / m2/EOD for 4 weeks and off. Breakthrough proteinuria may occur with intercurrent infection and usually does not require prednisolone if the child has no edema, remains well and the proteinuria resolves with resolution of the infection. If proteinuria persists, treat as relapse.

Management of frequent relapses Frequent relapses = 2 or more relapses within 6 months of initial response or 4 or more relapses within any 12 month period. Treatment Prednisolone 60 mg / m2 / day till urine albumin nil/trace for 3 days, then 40 mg / m2 / alternate mornings for 4 weeks. Taper prednisolone dose every 2 weeks and keep on as low alternate day dose as possible for 6 months. Should a child relapse while on low dose alternate day prednisolone, the child should be re-induced as for a relapse.

Management of steroid dependent nephrotic syndrome Steroid dependence = 2 consecutive relapses occurring during the period of steroid `taper or within 14 days of its cessation. Treatment If the child is not steroid toxic, re-induce with steroids and maintain on as low a dose of alternate day prednisolone as possible. If the child is steroid toxic (short stature, striae, cataracts, severe cushingoid features) consider cyclophosphamide therapy

E. Cyclophosphamide therapy This is indicated for the treatment of steroid dependent nephrotic syndrome with signs of steroid toxicity and should be started when the child is in remission following induction with corticosteroids. Dose: 2-3 mg/kg/day for 8-12 weeks Monitoring: FBC and Urine FEME two weekly. .

Relapses post cyclophosphamide Relapses after a course of cyclophosphamide is treated as for relapses after the initial diagnosis of nephrotic syndrome if the child does not exhibit any further signs of steroid toxicity. Should the relapse occur soon after a course of cyclophosphamide when the child is still steroid toxic, or the child again becomes steroid toxic after multiple relapses, then a paediatric nephrology opinion should be sought

Steroid resistant nephrotic syndrome / chronically nephrotic child Refer for renal biopsy. Specific treatment will depend on the histopathology. General management Control of edema - (a) Restriction of dietary sodium. (b) Diuretic e.g. Frusemide, Spironolactone. ACE inhibitor e.g. captopril to reduce proteinuria Control of hypertension. Penicillin prophylaxis. Monitor renal function.

Nephrotic Syndrome
Case Presentation

History
Identification data
Name Age Race Sex Occupation Address Date of admission Date of clerking Informant : Sakimmi Latiff : 21 years old : Malay : Male : Laborer : Kubang Kerian : 12-09-2006 : 14-09-2006 : Patients himself

Chief complaint
Facial puffiness and bilateral limbs oedema 2

weeks prior to admission.

History of presenting illness

Patient was apparently well until 4 weeks ago when he started to have facial puffiness and bilateral leg swelling. He sought medical consultation at HUSM. After the investigations have done, he was told to have renal problem by doctors. Medication was prescribed and he was required to follow up at HUSM.

His symptoms resolved after taking the medication. However he defaulted the follow up at HUSM

About 2 weeks ago, his symptoms reccured.

He discovered the limbs edema after waking up in the morning while the facial edema was noted by his mother at the time. The swelling was gradually increased in size especially when he was walking. It swelled in the morning and subsided in the evening initially but later the swelling appeared to persist for the whole day. However it was painless.

He also complaint of abdominal swelling 2days after the legs edema and facial puffiness.

On further questioning, he was known to take pil kuda(metamphetamine pill) previously but stop 1 year ago.

He denied of any upper respiratory tract or urinary tract infection like fever, sore throat, pharingitis or dysuria.

There was no joint pain, muscle ache, rashes, oral thrush,loin pain or haematuria. There was no paroxysmal nocturnal dyspnea, no orthopnea, no palpitation, no chest pain.
He had no history of Diabetes Mellitus or hypertension. No previous history of blood transfusion or other drug abuse noted.

Past medical and surgical history -nil of significant

Social history - no smoking - taking alcohol ( Beer once per week ) Drug history - pill kuda about 1 years ago

Food history - no allergic to any food

Family history He is 5th child out of 11 siblings. Father not working. His mother is factory worker. No family history of similar illness.

Physical examination
General examination: Inspection My patient is a medium bulid malay male, lying comfortable with one pillow. He is alert, conscious and well orientated with time, place and person. He is not in pain and respiratory distress. His nutritional and hydrational status is adequate. There is no gross deformity and abnormal movement can be found. Bilateral leg edema and facial puffiness was noted.

Vital sign : B/P : 120/80mmHg H/R : 70 bpm Temperature : 37.5C Respiratory rate : 15 per minute

Hand - palm is warm - No pallor - No palmar erythema - No peripheral cyanosis - No clubbing - No leuconychia - No half and half nail - No scar of needle injection in both fore arm and arm

Head - Conjunctiva is pink - No yellowish discoloration at sclera - Moist tongue - No central cyanosis - No ureamic fetor

Forearm and arm - No scratch mark - No bruising - No skin pigmentation No flapping tremor

Neck -No elevation of JVP

Lower limp -bilateral pitting edema until knee level Lymph nodes does not palpable

Gastrointestinal system : - Hepatomegaly :liver span: 14cm Spleenomegy :Spleen just palpable Dullness at Traubes space - Ascites : Shifting dullnes positives

Cardiorespiratory system

Inspection: - No spider naevi - No gynaecomastia -Jugular venous pulse not elevated Palpation Apex beat at 5th intercostal space, mid clavicular line

Auscultation: - S1S2 present, no murmur - Vesicular breath sound at both lung - Percussion nodes are resonance - No additional breath sound eg.Crepitation

Summary
Patient was a 21 years old, male admitted due to facial puffiness and bilateral leg swelling 2 weeks prior to admission. On physical examination, patient was noted to have bilateral leg swelling, facial puffiness, hepatomegaly, splenomegaly and ascites.

Provisional diagnosis

Nephrotic syndrome secondary to infection -Point towards : bilateral leg swelling facial puffiness ascites hepatosplenomegaly -Point against : no fever no jaundice

Differential Diagnosis

Liver disease (Hepatitis) Cardiac failure

Investigation
Full blood count - To assess general condition of patient, look for any anemia in chronic disease or infection - Results: - WBC- 12.5x109/L (increase) - Hb- 10.89/L (decrease) - RBC- 3.94x1012/L (decrease) - MCV- 82.5fl (normal) - MCH- 27.4pg (normal) - MCHC-20mmol/L (normal) - Platelet- 375x109/L (normal) - Lymphocytes- 5.4x109/L (increase) - Neutrophils- 5.7x 109/L (normal) - Anemic and suggestive of virus disease

BUSE
-

BUSE is to assess electrolyte imbalance Results: Creatinine- 75mmol/L (normal) Urea -5.8mmol/L (normal) Na-136 mmol/L (normal) K- 4.2mmol/L (normal) Calcium- 1.92 mmol/L (normal) Phosphate- 1.52mmol/L (normal)

Renal function test - creatinine clearance : 120mL/min (normal) - serum creatinine : 84mmol/L ( n)

Daily urine dipstick - To assess urinary protein or any possible glycosuria - Results: - Daily showed 4+ proteinuria 24 hours urine protein - 2.78g/L/24 hours ( increased )

Urine FEME and culture - To rule out urinary tract infection, red cells and red cell cast. - Culture- no growth - Pus cell- nil - Red blood cell- nil - Epithelial cell- 2 - Normal results not suggestive of glomerulonephritis

Liver Function Test: - To look for any liver disease - Total protein - 34g/dL ( decreased ) - Albumin - 14 g/dL (decreased ) - Globulin - 22 g/dL ( decreased ) - AST 18 u/L ( normal ) - ALT 8 u/L (normal ) - ALP 83 u/L (normal)

Erythrocyte Sedimentation Rate -To help in diagnosis infection, inflammation or malignancy such as TB, RA, connective tissue disease. Better as monitoring the inflammatory or malignancy Result: ESR-114mm/Hr- increase as normal within 10mm/Hr

Coagulation Test: To assess hypercoagulable states a complication in nephrotic syndrome Results: Prothrombin Time- 14.1s( increase) INR- 1.08 (normal) APTT- 41.3s (increase) - There was presence of hypercoagulable state - It may due to liver disease however the plaletet count and liver function test was normal

Cardiac Enzyme and ECG - To see any possible underlying cardiac problem that cause edematous - Results: CK- 65 U/mL, normal LDH- 240U/L, normal -Normal ECG

Lipid Profile: - Possible of hyperlipidemia in nephrotic syndrome - May associated with underlying cardiac disease - Results: - Triglyceride-7.05mmol/L (increase) - Cholesterol- 19.28 mmol/L (increase) - LDL-281IU/L (increase) - HDL- 0.48 mmmol/L (decrease)

Fasting blood glucose- 4.1mmol/L It is for detecting diabetes mellitus that cause nephropathy - Screen for HIV (Retrovirus)- Hepatitis B and C- negative - ANA( antinuclear antibody)- any SLE - Rheumatoid Factor- Inflammatory disease - Complement C3 and C4-may decrease in immune complex-mediated glomerulonephritis - Antistreptolysin titer may show evidence of streptococcus infection- negative
-

Renal Biopsy (plan for next week) - Histological diagnosis as to see whether the it will be responding to steroid such as in minimal changes glomerulonephritis

Ultrasound for Kidney, ureter and bladder (KUB) - Good as no radiation and contrast medium are used - To assess pelvicalyceal dilatation for any obstruction, any polycystic kidney, renal mass, intrarenal and perinephritic fluids.

Management
-

General measures: Monitor daily Blood pressure, Pulse rate, Temperature and Respiratory rate to detect any infection or dehydration Nephrotic Chart ( consist of daily BP, Weight, Urine albumin, Intake and output ) Input and Output chart to assess his fluid loss and balance Fluids restriction with 800cc daily to decrease edematous Diet with sodium restriction Frusemide IV 20mg BD for diuresis

Prophylaxis heparin 5000 unit BD as in nephrotic due to increase fibrinogen synthesis from liver and loss of antithrombin in urine will cause hypercoaguable state Atovastatin (HMG- COA reductase inhibitor) due to hyperlipidemia that will increase risk of myocardial disease and peripheral vascular disease If any infection, antibiotic should be given If any oliguria or defect in renal function test,albumin, mannitol or other diuretic should be given

NEPHROTIC SYNDROME

Definition
A collection of signs and symptoms A condition characterized by

massive edema heavy proteinuria(>40mg/m2 in children, >3.5g in adult ) Hypoalbuminemia(<25g/L) Hypercholesterolaemia (not needed in defination) susceptibility to recurrent infection

Definitions used for diagnosis and treatment of idiopathic NS:

Congenital NS : - NS presenting within the first 3 months of life Infantile NS: -NS presenting between 3 and 12 months of life

Remission: -Proteinuria <4mg/ m2/h or reagent strip = 0/trace for 3 consecutive days Relapse: -Proteinuria > 40mg/m2/ hour or reagent strip = ++ or more for 3 consecutives days

Frequent relapse - 2 or more relapses within 6 months of initial response or 4 or more relapses within any 12 months periods Steroid dependence - 2 consecutive relapses during steroid treatment or within 14 days after its cessation

Steroid sensitive NS - normalization of proteinuria within 4 weeks after start of standard initial therapy with daily, oral prednisolone Steroid resistant - failure to achieve remission in spite of 4 weeks of prednisolone 60mg/ m2/ day

Pathophysiology

Proteinuria Structural damage to the glomerular basement membrane Increase in size and number of pores Allowing passage of more and larger molecules PROTEINURIA Reduction of negatively charge components present in glomerular capillary wall which repel negatively charged protein molecules

Pathogenesis of oedema in hypoalbuminaemia A reduction in the concentration of osmotically active albumin molecules in the blood Reduction in the oncotic force that retains fluid within blood vessels Salt and water escape into the extravascular compartment OEDEMA

Hypoalbuminaemia

Lost through glomerulus In adult, urinary protein loss of 3-5g daily or more is required to cause hypoalbuminaemia In children, proportionately less proteinuria results in hypoalbuminaemia

Hyperlipidaemia
Increase synthesis of lipoprotein in the liver, abnormal transport of circulating lipids, and decreased catabolism

Increase risk of infection

Loss of immunoglobulin or low molecular weight complements in the urine

Causes of nephrotic syndrome

Primary

glomerular disease

All types of glomerulonephritis

Membranous disease is the most common form to cause nephrotic syndrome in adult Minimal change glomerular disease accounts for most cases in childhood

Glomerulopathy


1.
2.

Secondary glomerular disease

Systemic disease Henoch-Schonlein purpura Vasculitis (e.g. SLE) Infections (e.g. malaria ) Allergen (e.g. bee sting) Diabetic glomerular disease
Drugs Penicillamine, high dose captopril
Combines with a plasma protein to form an antigenic hapten, induces an immune complex mediated glomerulonephritis

3.

Toxins

Clinical signs of nephrotic syndrome

periorbital oedema (particularly on waking), the earliest sign scrotal, leg and ankle edema ascites SOB due to pleural effusions and abdominal distention

* neither elevation of JVP nor pulmonary oedema are features of nephrotic syndrome

Pattern of disease
Children
Usually primary glom disease Minimal change GN Treatment: usually start steroid without doing renal biopsy (80% of children response to prednisolone)

Adults
Usually secondary Membranous GN Treatment : Treat underlying cause

Usually recover

Progressive course

Steroid-sensitive nephrotic syndrome

Over 90% of children with nephrotic syndrome Proteinuria resolves with corticosteroid therapy Commoner in boys and inatopic families Often precipitatedby respiratory infections Features suggesting: Age between 1 and 10 years No macroscopic hamaturia Normal blood pressure Normal complement levels Normal renal function

Renal histology is usually normal on light microscopy but podocyte fusion is seen on electron microscopy minimal change disease Protein leak is mainly of low-molecular weight protein selective proteinuria Do not progress to renal failure

Prognosis
1/3 resolve directly 1/3 infrequent relapse 1/3 frequent relapses; steroid dependent

Steroid-resistant nephrotic syndrome

Managed by paediatric nephrologist Management of oedema Diuetic therapy Salt restriction Captopril (ACE inhibitor)

Cause Focal Segmental Glomerulosclerosis

Specific Features Most common Familial or idiopathic

Prognosis 30% progress to ESRF in 5 years; 20% response to cyclophosphamide, vincristine or cyclosporin Most remit spontaneously within 5 years May precede SLE Decline in renal function over many years

Membranous nephropathy

Associated with hepatitis B

Mesangiocapillary Glomerulonephritis (membranoproliferative glomerulonephritis

More common in older children Hematuria & low complement level present

Congenital Nephrotic syndrome

Present in the first three months of life Associated with early end-stage renal failure and a high mortality When renal failure develope, nephrectomy and dialysis are instituted until the child is large enough for transplantation

Complication

hypovolemia

a low urinary sodium ( < 20 mmol/L) and a high packed cell volume are indications ofhypovolemia during the initial phase of oedema formation the intravascular compartment may become volumedepleted complainsof abdominal pain and feel faint peripheral vasoconstriction and urinaty sodium retention

urgent treatment with IV albumin (4.5%) as child at risk of vascular thrombosis and shock

venous thrombosis

hypovolemia Sluggish blood flow Predispose to venous thrombosis Hypercoagulable state Loss of clotting factor (e.g. antithrombin) Increaase hepatic production of fibrinogen Increase blood viscosity from the raised hematocrit prolong bed rest should be avoided once renal vein thrombosis had occurred, prolong anticoagulation is required

Sepsis

Important cause of death in nephrotic syndrome Increase susceptibility to infection is due to loss of immunoglobulin in the urine Pneumococcal infections are particularly common and pneumococcal vaccine should be given Penicillin prophylaxis should be given to all children while they have hypoalbuminaemia

oliguric renal failure

a low blood volume and hypotension may lead to underperfused kidneys acute tubular necrosis may rapidly developed when renal ischemia occurs from other complications such as blood loss or septicaemia albumin infusion combined with mannitol or another diuretic may initiate a diuresis

Lipid abnormalities

Increased hepatic albumin synthesis is accompanied by increased cholesterol synthesis Hypertriglyceridaemia present in about 50% of patients increase risk of MI or peripheral vascular disease best treated with HMG-CoA reductase inhibitor

Modified ISKDC Regime

Scheme of treatment of idiopathic NS