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Definition
Nephrotic syndrome
Nephrotic syndrome is primarily a pediatric disorder and is 15 times more common in children than adults. The incidence is 2-3/100,000 children per year; and the majority of affected children will have steroid-sensitive minimal change disease.
-Heavy proteinuria (> 40 mg/m2/hour in children or a first morning protein:creatinine ratio of >2-3:1), -Hypoalbuminemia (<2.5 g/dL),
-Edema and
-Hyperlipidemia.
Nephrotic Syndrome
Edema
Hyperlipidemia
Pathogenesis
Damaged
Proteinuria
Pathogenesis of Proteinuria
Increase glomerular permeability for proteins due to loss of negative charged glycoprotein
Degree of protineuria:Mild less than 0.5g/m2/day Moderate 0.5 2g/m2/day Sever more than 2g/m2/day
Type of proteinuria:A-Selective proteinuria: where proteins of low molecular weight such as albumin, are excreted more readily than protein of HMW B-Non selective : LMW+HMW are lost in urine
Pathogenesis of Hyperlipidemia
Response to Hypoalbuminemia
reflex to liver
Decreased lipid catabolism as result of reduced lipoprotein lipase due to loss in urine
Hyperlipidemia
Pathogenesis of Edema
Intravascular volume antidiuretic hormone (ADH ) and aldosterone(ALD) water and sodium retention
Intravascular volume glomerular filtration rate (GFR) water and sodium retention
Proteinuria
Metabolic disorders with or without NS-Alagille syndrome -Alfa1 antitrypsin deficiency -Fabry disease -Glutaric acidemia -Glycogen storage disorder -Hurler syndrome -Lipoprotein disorders -Mitocondrial cytopathies -SCD
SECONDARY CAUSES : Infection : - Hepatitis B,C , HIV-1, Malaria, syphilis Toxoplasmosis Post Infectious Glomerular nephrotis Multisystem : - Henoch Schonlein purpura , Systemic Lupus erythmatosus Polyarteritis Nodosa Heredo familial:-Alport Syndrome Neoplasm : - Lymphoma , Leukemia Medication : - Non steroidal anti inflammatory drugs phenytoin, Interferon,Heroin Pencillamine, Lithium Allergens, Serum sickness toxoid, food allergens Insect bites
Childhood
NS can also be consequence of inflammatory glomerular disorders, normally associated with, features of nephritis e.g. vasulitis, Lupus nephritis, Membranoproliferative glomerulonephritis, IgA nephropathy
Classification:
B-Secondary NS:
C-Congenital NS: rare *1st 3month of life, only treatment renal transplantation
Clinical Manifestations
Clinical Manifestation
IN MCNS, The male preponderance of 2:1, age 2-6 years 1.Main manifestations:
2-Non-specific symptoms:
Typical Features Age 1-10 years Normotensive Normal Renal Function Microscopic haematuria (in up to 25%)
Atypical Features <1yr, >10years Hypertensive Elevated Creatinine Macroscopic haematuria Systemic, extra-renal disease symptoms Positive family history of NS Patients with atypical features are more likely to be unresponsive to steroid treatment. Those with atypical features at presentation should be discussed early with a Paediatric nephrologist. A renal biopsy may be indicated before receiving steroid treatment.
Nephrotic Syndrome
Complications
at
Complications of NS:
1-Infections:Infections is a major complication in children with NS. It frequently trigger relapses. Nephrotic patient are liable to infection because : A-loss of immunoglobins C3b, opsonins in urine. B-the edema fluid act as a culture medium. C-use immunosuppressive agents. D- malnutrition Common infection: URI, peritonitis, cellulitis and UTI Organisms: encapsulated Pneumococci, H.influenzae,Gram negative e.g E.coli
Complications of NS:
2-Hypercoagulability
Hypercoagulability of the blood leading to venous or arterial thrombosis. Hypercoagulability in Nephrotic syndrome caused by: 1-Higher concentration of I,II, V,VII,VIII,X and fibrinogen 2- Lower level of anticoagulant substance: antithrombin III 3-Decrease fibrinolysis. 4-Higher blood viscosity 5- Increased platelet aggregation 6- Overaggressive diuresis
Complications
3
of NS:
5 6
Diagnosis
proteinuria) Alternative : calculating the total protein-to-creatinine ratio 2-3:1(mg/mg) on urine specimen.
The history and physical examination Systemic disease Serologic studies- (ANA), complement, hepatitis B and
hepatitis C serologies and the measurement of cryoglobulins, serum or urine protein electrophoresis. Renal biopsy - may required at times.
CBC, serum albumin, serum proteins, calcium, Lipid profile, Coagulation tests
HEAT & ACETIC ACID TEST Principle-proteins are denatured & coagulated on heating to give white cloud precipitate. Method-take 2/3 of test tube with urine, heat only the upper part keeping lower part as control. Presence of phosphates, carbonates, proteins gives a white cloud formation. Add acetic acid 1-2 drops, if the cloud persists it indicates it is protein(acetic acid dissolves the carbonates/phosphates)
: No cloudiness Trace: Barely visible cloudiness. 1+ : definite cloud without granular flocculation 2+ : heavy and granular cloud without granular flocculation 3+ : dense cloud with marked flocculation. 4+ : thick curdy precipitation and coagulation
Other tests
Sulphosalicylic Dipsticks Esbachs
acid test
Kidney Biopsy
Considered in: 1-Secondary N.S 2-Frequent relapsing N.S 3-Steroid resistant N.S 4- Hematuria 5-Hypertension 6- Low GFR
Treatment
TREATMENT
TREATMENT
Hospitalization is necessary in the presence of: - gross edema, - respiratory distress - pleural effusion -peritonitis - unexplained fever 2. Bed rest is essential in gross edema 3. Salt and fluid restriction depend upon oedema 4. Diuretic is a double edged weapon, so it should be used with caution 5. Hydrochlorthizide would suffice in mild and moderate edema given as 4 mg/kg in a single dose. Furosemide (Lasix) at 2mg/kg 6. Spiranolactone should be combined with these diuretics.
INITIAL THERAPY Prednisolone 2 mg/kg as a single or divided doses for 4 weeks then give 2mg/kg as single dose in the morning on alternate days for the next 4 weeks. Then taper prednisolone by 10mg every 2 weeks. IF PERSISTENT PROTEINURIA after 4 weeks of daily therapy of steroid, continue same dose for next 4 weeks. No remission after 8 weeks of full dose of steroids, then label the child as steroid resistant. In this type of cases steroids should be tapered to 0.5 mg/kg. Simultaneously add cyclophosphamide 2 mg/kg/day. In case of steroid response but FREQUENT RELAPSES prednisolone is to be given as 2 mg/kg for 4 weeks and then as a single dose in the morning on alternate day for 4 weeks. After 8 weeks of steroid therapy, tapered slowly so that the entire course lasts for 6 months.
Alternative agent:
Treatment
Cytotoxic
drugs with corticosteroid: (for steroid dependent or steroid resistant) Cyclophosphamide (CTX):2.5 - 3 mg/kg/day for 8 weeks or equivalent. Maximum cumulative dose 168mg/kg. p.o. or intravenously Side effects: liver injury, inhibition of bone marrow, etc.
Cyclosporine
(for those failed responding to combination of steroid and cytotoxic drugs) Dose: 5mg/kg/d, bid, p.o. If successful, treatment continued for at least 1 year initially. Side effects: renal and liver toxic injury, expensive, etc.
Treatment
Mycophenolate
mofetil, MMF (for steroid dependent or steroid resistant) Dose:Up to 600mg /m2/dose twice daily. p.o. If successful, MMF treatment can be continued, with careful monitoring for 3 years, or more if clinically indicated.
COMPLICATIONS OF DRUGS
B.
Frusemide: Hypokalemia Hyponatremia Hyperuricemia Hypercalciuria Hypocalcemia Hypovolemia Tinnitus Deafness Acute interstitial nephritis C. Cyclophosphamide: Haemorrhagic Cystitis, Bone marrow depression, Alopecia.
Hypertension
Short acting Nifedipine 0.25 0.5 mg/kg per dose. Long acting Amlodipine 0.1mg/kg per day increasing in 0.1mg/kg increments every 48 hours to 0.4mg/kg/day. Protection against steroid induced gastric irritation should be considered for the duration of steroid treatment.
Gastro protection
DIET
DIET:
no added salt diet is advised & is important to reduce edema. Coconut rice, curd rice, lemon rice, beet-root, chappathi, dhall, sugar candy, boiled potato, carrot, cabbage, tomato and onion are accepted. Start with salt free diet in the presence of edema and then slowly add salt. WATER: Along with salt restriction water restriction is necessary to prevent dilutional hyponatremia. In mild edema intake is restricted to the urine output. In moderate edema intake is restricted to insensible water loss. In massive edema fluid intake is restricted to milk only equivalent to insensible water loss.
DIET
POTASSIUM:
Serum potassium abnormalities are infrequent in NS without renal failure. Hypokalemia is the consequence of indiscriminate diuretics. Add oral potassium in the presence of excessive tiredness or muscle weakness. Periodic serum potassium level estimation will be useful. PROTEIN: Normal protein diet is advised. In case of malnutrition increased protein intake is recommended. CALORIES: In the acute phase of Nephrotic Syndrome nutritional intake is reduced. In malnutrition caloric supplementation is necessary.
DIET
LIPID:
HDL levels are elevated in MCNS. Weight control is essential. Diet should contain cholesterol less than 250 mg/day. CALCIUM: Secondary to hypoalbuminemia there is low ionic calcium, which is responsible for cramps and tetany. Hence calcium intake of 800 mg/day either by diet or tablet with Vit.D is necessary. IRON : Iron supplementation is necessary in microcytic hypochromic anaemia.
Vaccines
Vaccines in NS:
Polyvalent pneumococcal vaccine (if not previously immunized) when the child is in remission and off daily prednisone therapy.
understand NS is chronic illness. optimistic attitude. Avoid doctor shopping. Urine Protein determinations- self monitoring is essential part of medical management. Use boiling or dipstick methods. First morning voiding is appropriate. Continue until child is in remission for 1 year. Follow up: The frequency of follow up will be dictated by the clinical course. Record keeping is also important aspect.
Thank you
Finnish-type
syndrome Focal segrnental glomerulosclerosis Diffuse mesangial sclerosis Denys-Drash syndrome Schimke immuno-osseous dysplasia
congenital nephrotic
Epidemiology
Levamisole may be beneficial for children with frequent relapses. It is less useful if steroid dependent. Dose 2.5 mg/kg/ on alternate days rounded to 25mg doses to max. 150mg. After treatment established for 4 weeks steroids can be tapered. If successful, treatment can continue for up to 3 years. Side effectsare rare and limited Idiosyncratic neutropenia reversible on discontinuing drug. Rash (erythema multiforme-like) GI intolerance. Monitoring FBC check monthly for first 3 months, at 6 months and 4-6 monthly thereafter.
Therapy
INITIAL THERAPY Prednisolone 2 mg/kg as a single or divided doses for 4 weeks then give 2mg/kg as single dose in the morning on alternate days for the next 4 weeks. Then taper prednisolone by 10mgm every 2 weeks. If there Is persistent proteinuria even after four weeks of daily therapy of steroid, continue the same dose for the next 4 weeks. If there is no remission even after 8 weeks of full dose of steroids, then lable the child as steroid resistant. In this type of cases steroids should be tapered to 0.5 mg/kg. Simultaneously add cyclophosphamide in a dose of 2 mg/kg/day. Care should be taken to have weekly W.B.C. count. In case of steroid response but when there is frequent relapse prednisolone is to be given as 2 mg/kg for 4 weeks and then as a single dose in the morning on alternate day for 4 weeks. After 8 weeks of steroid therapy, it should be tapered but slowly so that the entire course lasts for 6 months. When the child is resistant to Predinosolone and Cyclophosphamise, Chlorambucil, 2-3 mg/kg is given for 10 weeks.