Prepared by
Dr Rajesh T Eapen
ATLAS HOSPITAL
RUWI
Introduction
• Nephrotic syndrome (NS)
– Commonest glomerular disease
affecting children
– Frequently encountered in general
paediatrics
– Characterised by
• Significant proteinuria (early morning urine
protein to creatinine ratio > 200mg/mmol)
leading to
– Hypoalbuminaemia (plasma albumin of < 25g/l)
Paediatrics and child health 2010;20(1):36-42
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
– First morning protein : creatinine ratio of > 2-3 : 1
- Nelson Textbook of Paediatrics, Vol 2, 19th Edition, page 1801
Incidence
(paediatric ) ?
• 2 – 7 cases per 100,000 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
• Genetic
• Secondary
• Idiopathic or Primary
Genetic causes
• Finnish type Congenital NephroticSyndrome
• Focal Segmental Glomerulosclerosis
• Diffuse Mesangial Sclerosis
• Denys-Drash Syndrome
• Nail – Patella Syndrome
• Alport Syndrome
• Charcot-Marie-tooth disease
• Cockayne syndrome
• Laurence-Moon-Beidl-Bardet Syndrome
• Galloway-Mowat Syndrome
- Nelson Textbook of Paediatrics, Vol 2, 19th edition, page 1802, table 521-1
Secondary causes
• Congenital– Oligomeganephronia
• Infectious– Hepatitis (B,C) , HIV-1, Malaria, Syphilis, Toxoplasmosis
• Inflammatory– Glomerulonephritis
• Immunological– Castleman Disease, Kimura Disease, Bee sting, Food
allergens
• Neoplastic– Lymphoma, Leukemia
• Traumatic ( Drug induced )– Penicillamine, Gold, NSAIDS, Pamidronate, Mercury,
Lithium
- Nelson Textbook of Paediatrics, Vol 2,19th edition, page 1802, table 521
Idiopathic
• Minimal Change disease ( >80 % )
• Mesangial proliferation
• Focal segmental Glomerulosclerosis
• Membranous Nephropathy
• Membranoproliferative
glomerulonephritis
- Nelson Textbook of Paediatrics, Vol 2, 19th Edition, page 1804
Pathophysiology
Complex disturbances in
immune system
Genetic Mutations /
Mutations in proteins
Extensive effacement of podocyte foot processes
Increased permeability of the glomerular capillary wall
Massive proteinuria
Hypoalbuminaemia
Edema
PATHOPHYSIOLOGY
Clinical Features
alterations
CLINICAL
FEATURES
Minimal Change
Nephrotic
Syndrome
Focal
Segmental
Glomeruloscler
osis
Membranous
Nephropathy
Age ( yr ) 2 - 6 2 - 10 40 - 50
Sex ( M : F ) 2 : 1 1.3 : 1 2 : 1
Nephrotic
Syndrome
100 % 90 % 80 %
Asymptomatic
proteinuria
0 10 % 20 %
Hematuria 10 – 20 % 60 – 80 % 60 %
Hypertension 10 % 20 % early infrequent
Rate of
progression to
renal failure
Non progressive 10 yrs 50 % in 10 –
20 yrs
Associated
Conditions
Usually none None Renal vein
thrombosis,
SLE,
Hepatitis B- Nelson Textbook of Paediatrics, Vol 2 : page 1803, table 521-2
DIFFERENTIAL
DIAGNOSIS
• Protein losing enteropathy
• Hepatic failure
• Heart failure
• Acute/Chronic Glomerulonephritis
• Protein Malnutrition
• < 1 year old
• Family history of nephrotic Syndrome
• Hypertension
• Pulmonary edema
• Gross hematuria
• Extrarenal findings
Lab Investigations
• Urine Examination
• Complete Blood Count & Blood picture
• Renal parameters :
– Spot Urine Protein : Creatinine ratio
– Urinary protein excretion
– protein selectivity ratio
• Liver Function Test
• Renal Biopsy ???
• Urinalysis - 3+ to 4+ proteinuria
• Renal Function
– Spot UPC ratio > 2.0
– UPE > 40 mg/m2/hr
• Serum Creatinine – normal or elevated
• Serum albumin - < 2.5 gm/dl
• Serum Cholesterol/ TGA levels – elevated
• Serum Complement levels – Normal or
low
- Nelson Textbook of Paediatrics, Vol 2, 19th Edition, page 1804
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
Idiopathic Lab Findings
Minimal Change Nephrotic
Syndrome
Raised BUN in 15 – 30 %
Highly Selective proteinuria
Focal Segmental
Glomerulosclerosis
Raised BUN in 20 – 40 %
Membranous Nephropathy
Membranoproliferative
Glomerulonephritis
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
Membranoproliferative
GlomerulonephritisType 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
Management
Initial Episode
• High protein diet
• Salt moderation
• Treatment of infections
• If significant edema – diuretics Aldosterone antagonist ( Furosemide, spironolactone )
• Corticosteroid therapy with Prednisoloneor prednisone – ( 2mg/kg per day for 6 weeks followed by
1.5 mg/kg single morning dose on alternate days for 6 weeks )
Ghai Essential Paediatrics,8th edition, page 476, 477
Subsequent course
• Relapse
– Infrequent Relapsers : 3 or less
relapses per year
– Frequent Relapsers : 4 or more
relapses per year
• Steroid therapy
– Steroid dependant : relapse following
dose reduction or discontinuation
– Steroid resistant : Partial or no
response to initial treatment
Ghai Essential Paediatrics,8th edition, page 479
Management of Relapse
• Parent Education
• Symptomatic therapy for infections in
case of low grade proteinuria
• Persistent proteinuria ( 3 - 4+ ) –
– Prednisolone
( 2mg/kg/day until protein is negative for
3 days )
1.5 mg/kg on alternate days for 4
weeks )
Ghai Essential Paediatrics,8th edition, page 479
Frequent Relapses
• Alternate Day prednisolone
• Steroid sparing agents
– Levamisole ( 2 – 2.5 mg/kg )
– Cyclophosphamide ( 2 – 2.5 mg/kg/day)
– Mycophenolate Mofetil ( 20 – 25
mg/kg/day )
– Cyclosporin ( 4 – 5 mg/kg/day )
– Tacrolimus (0.1 – 0.2 mg/kg/day )
– Rituximab ( 375mg/m2 IV once a week )
Ghai Essential Paediatrics,8th edition, page 479, 480
Complications
• Edema
• Infections
• Thrombotic complications
• Hypovolaemia and Acute renal
Failure
• Steroid Toxicity
Ghai Essential Paediatrics,8th edition, page 480, 481
Steroid Resistant Nephrotic
Syndrome
• Diagnosis – Lack of response to prednisolonetherapy for 4 weeks
• Indication for renal biopsy , BBVS
• Etiology
– 10 – 20 % - Genetic ( Mutations in genes encoding podocyte proteins )
• Indications for mutational analysis :
– Congenital Nephrotic Syndrome
– Family History of SRNS
– Sporadic resistance to steroids
– Girls with steroid resistant FSGSGhai Essential Paediatrics,8th edition, page 481
Management of SRNS
• Steroids + calcineurin inhibitors + ACE
inhibitors / ARBs’ + HMG coenzyme-A +
Diuretics
Ghai Essential Paediatrics,8th edition, page 481, 482
Prognosis
• Steroid Responsive NS : Good
prognosis ( MCNS )
• Steroid Resistant NS : Poor prognosis
( FSGS )
- Nelson Textbook of Paediatrics, Vol 2, 19th Edition, page 1806
Congenital Nephrotic
Syndrome
• Presents in first 3 months of life
• Anasarca, hypoalbuminaemia, oliguria
‘Finnish’ Type Nephrotic Syndrome
• Antenatally detectable :
– Raised AFP in maternal serum and amniotic fluid
• Complications
– Failure o thrive
– Infections
– Hypothyroidism
– Renal Failure ( 2 – 3 yrs )
Ghai Essential Paediatrics,8th edition, page 482
Dietary management of ns
A balanced diet, adequate in
protein (1.5-2 g/kg) and calories
is recommended
Patients with persistent
proteinuria should receive 2-2.5
g/kg of protein daily
< 30% calories should be
derived from fat and saturated
fats avoided
• A ‘no added salt’ diet is advisable
in view of the salt and water
overload
• There is no evidence for use of a
high protein diet
• Children should be encouraged to
have a normal healthy diet
• Weight control
–In between meal snacks such as biscuits, crisps, and fizzy (high sugar) drinks should be avoided with low energy alternatives promoted
–Healthy eating advice should again be reinforced
• Steroid resistant nephroticsyndrome
–Vitamin supplementation and iron treatment may also be indicated
–Such children are often hospitalised for long periods and the clinical course may be complicated by diarrhoea and other nosocomial infections from the ward
prognosis
Due to loss of
proteins in the urineDue to ↓ oncotic
pressure
•Immunoglobulin
↑susceptibility to infection
•antithrombin III and proteins
C and S
Thromboembolism
•vit D–binding protein
vit D deficiency
•Transferrin
Iron deficiency anemia
•Hyperlipidaemia
•Hypovolemia
Acute renal failure
•Anasarca
risk of cellulitis, bacterial
peritonitis with ascites
,large pleural effusions
or pulmonary edema
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