Eka Laksmi Hidayati

Department of Child Health

Faculty of Medicine University of Indonesia Cipto Mangunkusomo Hospital
Jakarta

Glomerular capillary membranes

mechanism of proteinuria
A SIZE-SPECIFIC BARRIER
A CHARGE-SPECIFIC BARRIER

Idiopathic Nephrotic Syndrome

Heavy proteinuria

> 40 mg/m2/hour
> 50 mg/kg/day
Dipstix > 2+
Protein : creatinine ratio >2 (mg/mg)

Hypoalbuminemia < 2,5 g/dL

Generalized oedema
Hypercholesterolemia
(Haematuria or hypertension may be
present, but is not included in the
definition)
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Etiology
1. Congenital:
SN < 3 months

2. Primary/idiophatic:
3. Secondary:

hereditary and metabolic

immunologic diseases (LES, purpura Henoch Schoenlein)
infections (hepatitis B, malaria, syphilis, streptococcus),
toxin and alergen
neoplasma (malignum lymphoma, etc),
etc

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Congenital Nephrotic Syndrome

clinical onset in the first 3 months of life
proteinuria in utero or at birth
elevated amniotic fluid level of alpha-fetoprotein
before 20 weeks gestation
Classification :

Primary
Finnish type
Diffuse mesangial sclerosis
Minimal changes NS
Focal segmental glomerulosclerosis
Secondary
congenital syphilis, toxoplasmosis, cytomegalovirus
XY gonadal dysgenesis and Wilms tumour
nephroblastoma
etc
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Secondary Nephrotic Syndrome

Causes of secondary nephrotic syndrome
1.

Extrinsic antigens, drugs,

and toxins

Penicillamine
Mercury
Probenecid
Bees sting

Gold
Trimethadione
Volatile hydrocarbon
snake venom

2. Infections

Hepatitis B
Malaria
Leprosy

Syphilis
Filariasis
Schistosomiasis

3. Intrinsic antigens

Lupus erythematosus
Sarcoidosis
Transplantation

Syorgens syndrome
Renal tubular antigen
vasculitis syndrome

4. Neoplasms

Carcinoma
Leukemia

Lymphoma

5. Associations, possibly doubtful

Diabetes mellitus
Rheumatoid arthriris
Guillan Barre synd.

Renal vein thrombosis

Sickle cell disease

Epidemiology
Incidence
Incidence 2-7 new cases per 10,000
Prevalence 15.7 cases per 10,000

Age
MCD 2.5 years median age
FSGS 6 years median age

Sex
3:2 Boys : Girls in children <6 yo
Equal ratio in those older

Classification
Initial treatment: steroid
Classification of NS: Response of treatment
Classification :
- steroid sensitive nephrotic syndrome (SSNS)
- steroid resistant nephrotic syndrome (SSNS)
Remission:
- Urinary protein < 4 mg/ m2/hr or Albustix = 0/Trace or ratio
protein/creatinine < 0.2 mg/mg) for 3 consecutive days

Relapse:
- Urinary protein > 40 mg/m2/hr or Albustix > 2+ or
protein/creatinin ratio > 2 mg/mg) for 3 consecutive days
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Clinical classification of NS
Infrequent relapse NS:
SN relapse < 2 times in the first 6 months after initial
response or < 4 times per year
Frequent relapse NS:
Two or more relapses within 6 months of initial response or 4 or more
relapses within any 12 month period

Steroid dependent NS:

Two consecutive relapses occurring during corticosteroid treatment or within
14 days of its cessation

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Steroid resistant NS:

ISKDC (1970): No urinary remission within 4 weeks of

prednisone therapy 60 mg/m2/day and followed by an additional 4
weeks of alternate day prednisone at a dose 40 mg/m2/dose

Consensus 2001: No urinary remission within 4 weeks of prednisone

therapy 60 mg/m2/day

UKK Nefrologi IDAI 2008: No urinary remission within 4

weeks of prednisone therapy 60 mg/m2/day

Steroid toxic NS:

NS with side effects of steroid

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Glomerular filtration barrier

1. Mechanical/size barrier
Pore of glomerular capillary wall
-

Endotel
Basalis membrane
Epithel

: 1000
: 3000
: 250

2. Electricity/charge barrier
- Epithel
Sialic acid
- Endothel

negative charge

- Basalis membrane :Glucosaminoglycan

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T lymphocyte dysregulation:
cytokines, circulating factor(s)

Steroids
Cyclosporin
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Three parts of the glomerular capillary wall jointly

determine its functional properties-Deen 2004
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Scheme of podocyte
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PATHOPHYSIOLOGY
1. PROTEINURIA
2. PERMEABILITY IMPAIRMENT
MOLECULE IONIC CHARGE
MOLECULE SIZE

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PROTEINURIA
IgG
IgE
IgA
IgM
Fibrinogen

- Transferine
- Glob.Thyroxin
- Glob. Vit. D
- Coagulation factors
F VII, IX, XII
HYPOALBUMINAEMIA

B-lipoprot hyperlipidaemia
ONCOTIC PRESSURE
Lipiduria

OEDEMA
HYPOVOLAEMIA

Peripheral circulation collaps

Aldosteron

Na and H2O
retention

Hb

Packed cell vol

Viscocity

Vein thrombosis

Death
Renal perfusion
renin plasma Ureum
+
K
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Clinical manifestations
proteinuria
oedema: palpebra or pretibia
scrotum
ascites
pleural effusion
oliguria
hematuria
hypertension
due to renin secretion, aldosterone,
vasoconstrictor

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CLINICAL MANIFESTATIONS
Oedema (uptill 40% BW), ascites, hydrothorax,
scrotal oedema
Secondary infections : skin, peritonitis
Anaemia
Growth disturbances
Tetany (hypocalcaemia)
Hypovolemic shock
Vein thrombosis
Acute renal failure: oliguria/anuria, metabolic acidosis,
potassium

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 Hypoalbuminemia:

albuminuria
catabolisme albumin
albumin and amino acid intake

Protein in urine:

IgG
transferin
antithrombin III
plasminogen
antiplasmin
B factor
high density lipoprotein (HDL)
lecithine-cholesterol acyltransferase
vitamin D binding protein
thyroxin binding globulin
metal binding protein
transcortin, dll
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OEDEMA
Plasma oncotic coloid pressure e.c hypoalbuminemia
and transcapillary passage of fluid and solute to
subcutan tissue
intravascular volume and renin angiotensin system
Na and water retension oedema
Secretion of antidiuretic hormone (ADH)
Inhibition atrial natriuretik peptide (ANP)

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Nephrotic syndrome

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Generalized edema
(anasarca)

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Older child with

nephrotic syndrome
Pitting peripheral
oedema

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Nephrotic Syndrome

Ascites

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Nephrotic syndrome

Scrotal oedema

Labial oedema
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Hyperlipidemia:
cholesterol, trigliseride, phospholipid, fatty acid
low density lipoprotein (LDL) and very low density
lipoprotein (VLDL)
high densilty lipoprotein (HDL) plasma: normal

Increase of lipid and lipoprotein:

fatty and lipoprotein synthesis in liver
lipid catabolisme
lipoprotein lipase activity:
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Laboratory:
Massive proteinuria
Hypoalbuminemia and inverted albumin/globulin ratio
Hypercholesterolemia
Renal function: normal
creatinine and ureum: 32%
Haemoconcentrasion: Hb and Ht:
Thrombocytosis: 3%
Hematuria: 25%
Lipiduria
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Pathology Features
1.
2.
3.

4.
5.
6.

Minimal changes nephrotic syndrome

Focal segmental glomerulosclerosis (FSGS)
Proliferative glomerulonephritis
Focal proliferative glomerulonephritis

Diffuse mesangial proliferative glomerulonephritis

Exudative diffuse mesangial proliferative
glomerulonephritis
Mesangial proliferative glomerulonephritis with
crescent

Membranoproliferative glomerulonephritis
Membranous glomerulonephropathy
Advanced chronic glomerulonephritis
(Churg dkk, 1970; Habib, 1971)

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MINIMAL DISEASE

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PROLIFERATIVE DISEASE

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MEMBRANOUS DISEASE

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Treatment
Immunosupressive treatment
Glucocorticoid: Prednisone

Alkylating agents:

Cyclophosphamide
Chlorambucil

Combined immunospression
Antiproliferative agents: azathioprine, MMF
Calcineurin inhibitors: cyclosporine
FK056

Nonsteroid antiinflammatory drugs

Antiproteinuric treatment ACE inhibitors
Lipid lowering agents
Supportive treatment

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McBryde KD, Kershaw DB, Smoyer WE. Curr Probl Pediatr 2001;31:275-307
Niaudet P. Pediatric Nephrology,2004, p. 558-73

Supportive treatment
General

Bed rest
Mantoux test
Elimination of focus infection: teeth, ears, worms

Dietary recommendation
Diuretics
Prevention and therapy of:
infections
thromboembolic

Treatment of:

hypovolemia

hypertension
hyperlipidemia
McBryde KD, Kershaw DB, Smoyer WE. Curr Probl Pediatr 2001;31:275-307
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Niaudet P. Pediatric Nephrology,2004, p. 558-73

Corticosteroid
Prednisone
SN inisial:

a. ISKDC protocol (1970) or modification:

Prednisone full dose 60 mg/m2 BSA/d or 2
mg/kgbw/d (max. 80 mg/d) 4 weeks.
Followed prednisone 40 mg/m2BSA/d or 2/3 full
dose (1,5 mg/kgbw/d) for 4 weeks with
intermitten dose (3 consecutive day) or
alternating dose (alternate day in the morning)
Remission
: 80% after prednisone 2 weeks
94% after prednisone 4 weeks
Initial treatment
: complete remission: 94% patients,
relapse 60-70% and frequent relapse
50%

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4 weeks

4 weeks

Remission(+)
Proteinuria (-)
Edema (-)

Alternating dose
(AD)

Remission (-): Steroid resistant

Other immunosupressant
Prednisone FD: 60 mg/m2 BSA/day
Prednisone AD: 40 mg/m2 BSA/say

Fig: Initial treatment with corticosteroid

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b. APN Jerman (1988):

Prednisone 12 weeksu: FD 6 weeks and AD 6 weeks
Results: - remission: longer
- relapse rate : 36,2% vs 81%

SN relapse:
prednisone full dose until remission (max 4 weeks)
and prednisone 2/3 full dose 4 weeks

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RECOMMENDED DOSAGES
Prednisone
DAILY

: 60 mg/m2/day in 3 divided dose

Intermittent

: 40 mg/m2/day in 3 divided dose,

3 executive days in a week
: 40 mg/m2/day single dose

Alternatively

Cyclophosphamide
2-3 mg/kg/day for 8 12 weeks in combination with steroid
intermittent

Chlorambucil
0,1--0,2 mg/kg/day in divided dose with steroid AD
0,1
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Others Immunosupressant

Cyclosporine
Mycophenolate Mofetil (MMF)
Tacrolimus
Mizoribine
Vincristine
Rituximab
Purine analog:
Azatioprine
6-merkaptopurin
6-thioguanin

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Hospitalization
NS with:
-

schock
anasarca oedema
severe hypertension
vomiting
renal failure
severe infection: peritonitis
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Referred
Reason for referral

Diagnostic: FSGS, secondary NS

Adverse effect of steroid / cytostatic
Renal biopsy

Cases to be referred

Age < 12 months (Congenital or infantile NS)

Mixed nephrotic dan nephritic
Persistent hypertension
Hypocomplementemia
Severe complications
Dependent steroid, frequent relapses
Resistant steroid

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COMPLICATIONS

Hypovolemia
Schock
Acute renal failure
Infections
Thrombosis
Electrolyte imbalance
Malnutrition
Delayed of growth
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THE CLINICAL RESPONS OF MINIMAL CHANGES

PATIENTS TO STEROID (ISKDC)
Minimal Change 100%
Responsive 93%
Norelaps
36%

Infrequent Frequent
Relapser
Relapser
39%
18%

Non responsive
5%

Early Non responsive 7%

Late responsive
5%

Non-responsive
2%

(Kidney Int. 13-43, 1978)

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PROGNOSIS
Prognosis:
response to steroid > pathology anatomy.
Prognosis during 20 years (ISKDC,1978):
MCNS
: 4-5% ESRD
FSGS
: 25% ESRD in 5 years
Fakhouri et al.(2003):
Cohort study SSNS:

42,2% children relapse in adult

higher age, relapse become rare
< 11 years : relapse 1.07
12-17 years : relapse 0,79
> 18 years : relapse 0,5.
> 11 years : 64,3% no relapse
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Prognosis .
Mortality
1940s- 40% 1 year mortality
Nowadays 1-2%
Main causes
Infection
Thrombosis

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Thank you

Congenital Nephrotic Syndrome

the majority of cases

autosomal recessive inheritance

incidence in Finland: 12 cases/100 000 births
born prematurely 35-38 weeks
small for gestational age
placenta weighing > 25% birth weight
breech presentation, fetal asphyxia
widened cranial sutures, large fontanelles, pliable
cartilagenous tissue
small nose, wide-set eyes, low-set ears

Prognosis : infaust
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