Nephrotic Syndrome

Dr. Vinit Warthe

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.

The characteristic features of nephrotic syndrome are

-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

Massive Proteinuria Hypoalbuminemia

Edema

Hyperlipidemia

Pathogenesis

Pathogenesis of Nephrotic syndrome

Damaged

Proteinuria

Maintain barrier function

McBryde KD. Pediatric steroid-resistant nephrotic syndrome. Curr Probl Pediatr.2001;31:275-307

How many pathological types causes nephrotic syndrome?

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

synthesis of generalize protein ( including lipoprotein )

lipid in the liver

the lipoprotein high molecular weight no loss in urine

Decreased lipid catabolism as result of reduced lipoprotein lipase due to loss in urine

Hyperlipidemia

Pathogenesis of Edema

Reduction plasma colloid osmotic pressure secondary to hypoalbuminemia

Intravascular volume antidiuretic hormone (ADH ) and aldosterone(ALD) water and sodium retention

Intravascular volume glomerular filtration rate (GFR) water and sodium retention

Causes of Nephrotic syndrome

GENETIC DISORDERS NS (Typical) -Finnish type congenital NS -Focal segmental glomerulosclerosis -Diffuse Mesingial scleosis -Denys Drash syndrome

Proteinuria

with or without NS-Nail Patella syndrome -Alport Syndrome

Causes of Nephrotic syndrome

Multisystem syndromes with or without NS-Galloway Mowat syndrome -Charcot Marie Tooth disease -Jeune syndrome -Cockayne Syndrome -Laurence Moon Biedl Bardet Syndrome

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

Causes of Nephrotic syndrome

Idiopathic NS -Minimal Change NS -Focal segmental glomerularsclerosis -Membranous Nephropathy

Causes of Nephrotic syndrome

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:

A-Primary Idiopathic NS (INS): majority

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:

Edema (varying degrees) is the common symptom

Local edema: edema in face , around eyes( Periorbital swelling), in lower extremities. Generalized edema (anasarca): ascities, genital edema.

2-Non-specific symptoms:

Fatigue and lethargy

loss of appetite, nausea and vomiting ,abdominal pain, diarrhea, body weight increase, urine output decrease pleural effusion (respiratory distress)

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

Differential Diagnosis of NS:

D/D of generalized edema:

1-Proteinlosing enteropathy 2-Hepatic Failure. 4-Protein energy malnutrition CCF

5-Acute and chronic GN

6-urticaria? Angio edema

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:

ARF: pre-renal and renal

cardiovascular disease :-Hyperlipidemia, may be a risk factor for cardiovascular disease.

Hypovolemic shock

5 6

Others: growth retardation, malnutrition, adrenal cortical insufficiency

Diagnosis

24-hour urine collection- >3.5 g/day (nephrotic-range

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.

BUN, creatinine, creatinin clearance. Na, K, bicarbonates, chloride

CBC, serum albumin, serum proteins, calcium, Lipid profile, Coagulation tests

Tests for proteins

Test

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)

Grade the turbidity as follows:

Negative

: 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

albuminometer- for quantitative estimation of proteins

Esbachs Albuminometer for 24 hour albumin

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

Common definitions to define the course of Nephrotic syndrome

Remission -Urinary protein excretion <40 mg/m/h; nil or trace by dipstick on spot sample for 3 consecutive days Relapse - Urinary protein excretion >40 mg/m/h; > 3+ by dipstick for 3 consecutive days Frequent relapses- Two or more relapses in 6 months of initial response; 4 or more relapses in any 12 month period Steroid dependence - Occurrence of 2 consecutive relapses during steroid therapy or within 2 week of its cessation Steroid resistance - Failure to achieve remission after 4 week of daily therapy with oral prednisolone at a dose of 2 mg/kg/day

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:

When can be used:

Steroid-dependent patients, frequent relapsers, and steroidresistant patients.

Cyclophosphamide Pulse steroids Cyclosporin A Tacrolimus

Mycophenolate mofetil, MMF

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 A. Steroids:

-Pseudo tumor cerebri -Cataract -Cushingoid facies -Unmasking of tuberculous focus -Peptic ulcer -Diabetes mellitus -Hypertension -Aseptic necrosis of femoral head -Stunted growth -Osteoporosis -Adrenal gland suppression -Hyperglycemia -Myopathy -Poor healing of wound. -Hirsutism -Thromboembolism

COMPLICATIONS OF DRUGS
B.

Frusemide: Hypokalemia Hyponatremia Hyperuricemia Hypercalciuria Hypocalcemia Hypovolemia Tinnitus Deafness Acute interstitial nephritis C. Cyclophosphamide: Haemorrhagic Cystitis, Bone marrow depression, Alopecia.

Indication use of albumin

Albumin + Lasix (20 % salt poor) Severe edema Ascites Pleural effusion Genital edema Low serum albumin

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.

Children with a negative varicella titer should be given varicella vaccine.

Other aspects of management

Attitude-

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.