Dr. Naveen G Nadig Associate Professor Dept. of Paediatrics SSIMS & RC Davanagere

Nephrotic Syndrome

It is a symptom complex characterised by massive proteinuria, hypoproteinaemia, hyperlipidaemia or cholesterolaemia, and oedema.

DEFINITION

ISKDC (International Study of Kidney Diseases in Children) defines nephrotic syndrome as a massive proteinuria of 40 mg/m2 /hr, hypoalbuminemia 25g/L, hypercholestreolaemia 220mg/dl and with or without oedema.

AETIOLOGY

I. Primary causes Primarily glomerular diseases1. Minimal change nephrotic syndrome (MCNS)2. Mesangial proliferative glomerulonephritis 3. Focal and segmental glomerulosclerosis (FSGS)4. Membranoproliferative glomerulonephritis5. Crescentric glomerulonephritis6. Membranous nephropathy

Secondary1. Infections • Post streptococcal glomerulonephritis• Shunt nephritis• Infective endocarditis• Staphylococcus aureus• Mycobacterium tuberculosis• Leprosy• Syphilis

2. Viral – Infectious mononucleosis– Cytomegalovirus– Hepatitis B virus– Varicella– HIV

3. Parasitic Protozoal• Plasmodium malariae• Plasmodium falciparum• Toxoplasmosis

Helminths

4. Autoimmune disorders Dermatomyositis SLE Rheumatoid arthritis Polyarteritis nodosa Goodpasture’s syndrome Haemolytic uraemic syndrome Henoch-schonlein purpura

5. Drugs and toxins Bismuth Gold Mercury Penicillamine Heroin Phenytoin Ethosuccimide Methimazole Lithium Captopril

6. Toxins and pollen Bee sting Snake bite Anti snake venom

7. Metabolic Amyloidosis Diabetes mellitus Myxoedema

8. Heart diseases Congestive cardiac failure Infective endocarditis Constrictive pericarditis Congenital heart diseases

9. Malignant disorders Hodgkin’s Non-Hodgkin’s Lymphomas Carcinomas

10. Congenital conditions Congenital nephrotic syndrome (Finnish

variety) Alport’s syndrome

Nephrotic Syndrome in InfantsPrimary causes – congenital and secondary causes.Primary Cause 1. Congenital nephrotic syndrome.2. Minimal changes nephrotic syndrome.3. Nephrosclerosis4. Focal and segmental glomerulosclerosis

Secondary causes Congenital syphilis Toxoplasmosis cytomegalovirus

Annual incidence of nephrotic syndrome is 2/1 lakh up to 16 years of age

Pathophysiology

Massive proteinuria and its parameters

1.Urine parameters for massive proteinuria Urine 1 + : 30 mg/dL 2 + : 100 mg/dL 3 + : 300 mg/dL 4 + : more than 2 g/dL

2. 24 – hours urinary protein estimation Mild proteinuria : less than 500 mg/m2 /day Moderate proteinuria : 500 - 1000 mg/m2 /day Massive proteinuria : 1000 mg/m2 /day

3. Massive proteinuria : 40 mg/m2 /hr

Mechanism of Massive proteinuria 1.Loss of negatively charged sialoproteins and

glycoproteins2.Increased size of the pores3.Loss of foot process4.Increased excretion or decreased absorption5.Platelet factor released in the glomeruli from

platelet

Hypoproteinaemia1.It is due to increased loss not in the urine but

also from the gut.2.Inadequate synthesis.3.Increased catabolism of protein in he kidney

itself and in other sites like intestines.

• Hyperlipidaemia 1. The VLDL content is more increased in nephrotic

syndrome but the triglyceride levels are decreased when the albumin level is less then 1g.

2. Loss of lipoprotein lipase enzyme in urine3. Decrease conversion of VLDL into LDL by decrease of

lipoprotein lipase4. Loss of apolipoprotein in the urine, which normally

activates lipoprotein lipase enzyme.5. Decrease levels of HDL, which also destroys VLDL.6. Increased synthesis of lipoproteins.

Oedema1. Decrease of oncotic pressure due to hypoproteinaemia

leading to increase production of renin- angiotensin, ADH. So, there is an increased absorption of sodium and water from renal tubules.

2. Defective excretion of sodium and water from the kidney due to dysfunction.

3. Circulation of an unknown antigen causing increased capillary permeability.

4. Decreased production of atrial natriuretic peptide in nephrotic syndrome, which causes retention of sodium and water.

Pathogenesis1. IgE medicated theory: IgE levels are increased in pollen

season during relapsed cases.2. T cell dysfunction may be responsible for production of

lymphokines, which causes nephrotic syndrome. Eg. Hodgkin’s disease

3. Cytokines may be responsible for causing increased capillary permeability.

4. Role of antibodies5. Role of genetics : The exact genetic role is not known but

familial tendency is present in 2-8%. HLA – B12 patients are prone for relapses . HLA-B8 patients are less likely to relapse after treatment

with cyclophosphamide.

PATHOLOGY OF NEPHROTIC SYNDROME

1.Minimal change nephrotic syndrome Thickening of the basement membrane Effacement of food process Deposition of IgM and C3.

2. Mesangial proliferation The above changes are present . Maximum deposition of mesangial cells and

matrix. Deposition of IgM and C3.

3. Focal segmental glomerulosclerosis: Sclerosis of glomeruli and juxtaglomerular apparatus.

Clinical Features Predisposing factors. Viral upper respiratory tract infections can induce

nephrotic syndrome. Age group: The incidence is more between 2 – 6 years. Sex: Male children are more prone for nephrotic

syndrome. The sex ratio from male to female is 2 to 3:1. In adolescence and adults the sex ratio is equal.

Periorbital oedema is followed by anasarca. Respiratory distress may be due to pleural effusion and

tense ascites. Oliguria may be present. Diarrhoea may be due to congestion of the intestines.

ON EXAMINATION OF THE PATIENT

• Anasarca is present.• Wet fundus.• Transverse white lines on nails – Mees lines or

Muercke lines.• Signs of ascites and pleural effusion may be

present.

DIFFERENTIAL DIAGNOSIS

1. Acute glomerulonephritis2. Congestive cardiac failure3. Protein – energy malnutrition4. Cirrhosis of liver5. Protein losing enteropathy.

INVESTIGATIONS

1.Urine examination for: Albumin Sugar Deposits 24 hours urine for protein estimation Urine protein/creatine ratio Urine protein selectivity Oval fat bodies and waxy or hyaline casts

2. Blood – total proteins Albumin / globulin ratio Serum cholesterol

3. Mantoux test4. X-ray chest To exclude

tuberculosis5. Urine for culture/sensitivity – to exclude UTI

MANAGMENT

Initial management1.Admit the patient for the following reasons:

For establishment of the diagnosis For exclusion of infections To wait for spontaneous remission

2. Role of diuretics: Indications for diuretics:a. To prevent the breakdown of skinb. To prevent secondary infections due to break

down of skinc. GIT and respiratory embarrassmentd. Urethral obstruction due to massive oedema of

scrotum

Mild to moderate oedema – chlorothiazide 10 – 40 mg/kg/day in divided doses. Severe oedema – furosemide 1 – 2 mg/kg/dose 8th hourly or 6th hourly.

If the patient does not respond to furosemide, metalozone 0.2 – 0.4 mg/kg/day in divided doses is added.

If the patient develops hypokalaemia, either potassium supplementation or spironolactone 3 – 4 mg/kg/day in 4 divided doses can be given.

3. Role of dietNormal protein diet 1.5 – 2g/kg/day is suggested.If nephrotic syndrome is associated with malnutrition, high protein diet 3 – 5 g/kg/day can be given.

a. SodiumThere is no proof that salt content in diet can

aggravate oedema. But in severe oedema, salt restricted diet is advised with no added salt.

b. Fat content in dietLow fat diet is advised.

Treatment after confirmation by corticosteroids1.ISKDC regimen

To start with 60 mg/m2/day in 3 divided doses for 4 weeks followed by 40 mg/m2 on alternate days 4 weeks.For relapses 60 mg/m2/day in 3 divided doses till urine is free of proteins for three consecutive days, followed by 40 mg/m2 on alternate days for 4 weeks.

3. Nelson’s textbook of Paediatrics regimen1 – 2 mg/kg of prednisolone is given in 3 or 4 divided doses for a period of 4 weeks.After 1 month, examine the urine for proteins for 5 consecutive days. If the urine is free of protein or less than 2+, the same is given as a single dose on alternate days before 8 AM after breakfast for 3 - 6 months.

Advantages with alternate day regimen1.Complications are less.2.It can prevent frequent relapses.3.It will not alter the pituitary-adrenal axis.4.Drug can be stopped abruptly.

ISKDC Explanation of Some of the terms1. Response : Urine is free of proteins in 8 weeks.2. Remission : Urine protein is less than 1+ or less than 4

mg/m2/hour.3. Early response: Patient who responds to steroids within 8

weeks.4. Late response : respond after 8 weeks.5. Relapse ; Proteinuria 2 + or 40 mg/m2/hr for 1 week6. Frequent relapse : More than 2 relapses in 6months or 3

relapses in one year.7. Early relapse : Initial early responders who relapse during 8

weeks of therapy.8. Steroid dependent : 2 consecutive relapses while therapy

being decreased or consecutive relapse within 2 weeks of stoppage of steroid therapy.

Other Drug Used for Resistant Cause

1. Cyclophosphamide2. Levamisole3. Dipyridamole4. ACE inhibitors5. Azathioprine6. Cyclosporine7. Methyl prednisolone8. Dexamethasone9. IV immunoglobulin10. Fish oil11. Non steroidal anti inflammatory agents12. Plasmapheresis

COMPLICATIONS

Due to Disease1.Growth failure 2.PEM due to loss of proteins3.Acute renal failure4.Chronic renal failure5.Spontaneous bacterial peritonitis6.Coagulation defects

Complications Due to Therapy1.Corticosteroids

Cushingoid syndrome Hypertension due to salt retention Osteoporosis Susceptible to infections

2. Cyclophosphamide Alopecia Leucopenia Infertility Haemorrhagic cystitis Susceptibility to infections