Eka Laksmi HidayatiDepartment of Child Health
Faculty of Medicine University of Indonesia –Cipto Mangunkusomo HospitalJakarta
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Glomerular capillary membranesGlomerular capillary membranesmmechanism of proteinuriaechanism of proteinuria
A SIZE-SPECIFIC BARRIERA CHARGE-SPECIFIC BARRIER
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IdiopathicIdiopathic NephroticNephrotic SyndromeSyndrome
• 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 thedefinition)
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• 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 thedefinition)
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
Etiology
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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
Congenital Nephrotic SyndromeCongenital 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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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
Secondary Nephrotic SyndromeCauses of secondary nephrotic syndrome
1. Extrinsic antigens, drugs,and toxins
2. Infections
•Penicillamine •Gold•Mercury •Trimethadione•Probenecid •Volatile hydrocarbon•Bee’s sting •snake venom
•Hepatitis B •Syphilis•Malaria •Filariasis•Leprosy •Schistosomiasis
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3. Intrinsic antigens
4. Neoplasms
5. Associations, possibly doubtful
•Lupus erythematosus •Syorgen’s syndrome•Sarcoidosis •Renal tubular antigen•Transplantation •vasculitis syndrome
•Carcinoma •Lymphoma•Leukemia
•Diabetes mellitus •Renal vein thrombosis•Rheumatoid arthriris •Sickle cell disease•Guillan Barre synd.
EpidemiologyEpidemiology• 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
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• 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
Initial treatment: steroidClassification 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 ratioprotein/creatinine < 0.2 mg/mg) for 3 consecutive days
Relapse:- Urinary protein > 40 mg/m2/hr or Albustix > 2+ orprotein/creatinin ratio > 2 mg/mg) for 3 consecutive days
Classification
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Initial treatment: steroidClassification 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 ratioprotein/creatinine < 0.2 mg/mg) for 3 consecutive days
Relapse:- Urinary protein > 40 mg/m2/hr or Albustix > 2+ orprotein/creatinin ratio > 2 mg/mg) for 3 consecutive days
Infrequent relapse NS:SN relapse < 2 times in the first 6 months after initialresponse or < 4 times per year
Frequent relapse NS:Two or more relapses within 6 months of initial response or 4 or morerelapses within any 12 month period
Steroid dependent NS:Two consecutive relapses occurring during corticosteroid treatment or within14 days of its cessation
Clinical classification of NS
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Infrequent relapse NS:SN relapse < 2 times in the first 6 months after initialresponse or < 4 times per year
Frequent relapse NS:Two or more relapses within 6 months of initial response or 4 or morerelapses within any 12 month period
Steroid dependent NS:Two consecutive relapses occurring during corticosteroid treatment or within14 days of its cessation
Steroid resistant NS: ISKDC (1970): No urinary remission within 4 weeks of
prednisone therapy 60 mg/m2/day and followed by an additional 4weeks of alternate day prednisone at a dose 40 mg/m2/dose
Consensus 2001: No urinary remission within 4 weeks of prednisonetherapy 60 mg/m2/day
UKK Nefrologi IDAI 2008: No urinary remission within 4weeks of prednisone therapy 60 mg/m2/day
Steroid toxic NS:NS with side effects of steroid
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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 4weeks of alternate day prednisone at a dose 40 mg/m2/dose
Consensus 2001: No urinary remission within 4 weeks of prednisonetherapy 60 mg/m2/day
UKK Nefrologi IDAI 2008: No urinary remission within 4weeks of prednisone therapy 60 mg/m2/day
Steroid toxic NS:NS with side effects of steroid
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Glomerular filtration barrierGlomerular filtration barrier1. Mechanical/size barrier
Pore of glomerular capillary wall- Endotel : 1000 Å- Basalis membrane : 3000 Å- Epithel : 250 Å
2. Electricity/charge barrier- Epithel
Sialic acid- Endothel negative charge
- Basalis membrane :Glucosaminoglycan14
1. Mechanical/size barrierPore of glomerular capillary wall
- Endotel : 1000 Å- Basalis membrane : 3000 Å- Epithel : 250 Å
2. Electricity/charge barrier- Epithel
Sialic acid- Endothel negative charge
- Basalis membrane :Glucosaminoglycan
T lymphocyte dysregulation:T lymphocyte dysregulation:cytokines, circulating factor(s)cytokines, circulating factor(s)
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SteroidsCyclosporin
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Three parts of the glomerular capillary wall jointlydetermine its functional properties-Deen 2004
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Scheme of podocyteScheme of podocyte
PATHOPHYSIOLOGY
1. PROTEINURIA2. PERMEABILITY IMPAIRMENT
• MOLECULE IONIC CHARGE• MOLECULE SIZE
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1. PROTEINURIA2. PERMEABILITY IMPAIRMENT
• MOLECULE IONIC CHARGE• MOLECULE SIZE
PROTEINURIA
- Transferine- Glob.Thyroxin- Glob. Vit. D- Coagulation factorsF VII, IX, XII
IgGIgE IgA IgM Fibrinogen
HYPOALBUMINAEMIA
B-lipoprot hyperlipidaemia
ONCOTIC PRESSURE
OEDEMALipiduria
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OEDEMAHYPOVOLAEMIA
Lipiduria
Aldosteron
Na and H2Oretention
Hb
Packed cell vol
Viscocity
Vein thrombosis
Peripheral circulation collaps
Death
Renal perfusion
renin plasma Ureum+K
Clinical manifestationsClinical manifestations
proteinuria oedema: palpebra or pretibia
scrotum ascites pleural effusion
oliguria hematuria hypertension
due to renin secretion, aldosterone, vasoconstrictor
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proteinuria oedema: palpebra or pretibia
scrotum ascites pleural effusion
oliguria hematuria hypertension
due to renin secretion, aldosterone, vasoconstrictor
CLINICAL MANIFESTATIONS……
Oedema (uptill 40% BW), ascites, hydrothorax,scrotal oedema
Secondary infections : skin, peritonitisAnaemiaGrowth disturbancesTetany (hypocalcaemia)Hypovolemic shockVein thrombosisAcute renal failure: oliguria/anuria, metabolic acidosis,
potassium
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Oedema (uptill 40% BW), ascites, hydrothorax,scrotal oedema
Secondary infections : skin, peritonitisAnaemiaGrowth disturbancesTetany (hypocalcaemia)Hypovolemic shockVein thrombosisAcute renal failure: oliguria/anuria, metabolic acidosis,
potassium
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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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
OEDEMAPlasma oncotic coloid pressure e.c hypoalbuminemia
and transcapillary passage of fluid and solute tosubcutan 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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OEDEMAPlasma oncotic coloid pressure e.c hypoalbuminemia
and transcapillary passage of fluid and solute tosubcutan tissue
intravascular volume and renin angiotensin system Na and water retension oedema
Secretion of antidiuretic hormone (ADH)
Inhibition atrial natriuretik peptide (ANP)
Nephrotic syndromeNephrotic syndrome
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Generalized edema(anasarca)
Older child withOlder child withnephrotic syndromenephrotic syndrome
Pitting peripheraloedema
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Pitting peripheraloedema
Nephrotic SyndromeNephrotic Syndrome
27Ascites
Nephrotic syndromeNephrotic syndrome
28Scrotal oedema Labial oedema
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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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:
Massive proteinuriaHypoalbuminemia and inverted albumin/globulin ratioHypercholesterolemiaRenal function: normal
creatinine and ureum: 32%Haemoconcentrasion: Hb and Ht:
Thrombocytosis: 3%Hematuria: 25%Lipiduria
Laboratory:
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Massive proteinuriaHypoalbuminemia and inverted albumin/globulin ratioHypercholesterolemiaRenal function: normal
creatinine and ureum: 32%Haemoconcentrasion: Hb and Ht:
Thrombocytosis: 3%Hematuria: 25%Lipiduria
Pathology FeaturesPathology Features1. Minimal changes nephrotic syndrome2. Focal segmental glomerulosclerosis (FSGS)3. Proliferative glomerulonephritis
Focal proliferative glomerulonephritis Diffuse mesangial proliferative glomerulonephritis Exudative diffuse mesangial proliferativeglomerulonephritis Mesangial proliferative glomerulonephritis withcrescent
4. Membranoproliferative glomerulonephritis5. Membranous glomerulonephropathy6. Advanced chronic glomerulonephritis
(Churg dkk, 1970; Habib, 1971)31
1. Minimal changes nephrotic syndrome2. Focal segmental glomerulosclerosis (FSGS)3. Proliferative glomerulonephritis
Focal proliferative glomerulonephritis Diffuse mesangial proliferative glomerulonephritis Exudative diffuse mesangial proliferativeglomerulonephritis Mesangial proliferative glomerulonephritis withcrescent
4. Membranoproliferative glomerulonephritis5. Membranous glomerulonephropathy6. Advanced chronic glomerulonephritis
(Churg dkk, 1970; Habib, 1971)
MINIMAL DISEASE
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PROLIFERATIVE DISEASE
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MEMBRANOUS DISEASE
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TreatmentTreatment• 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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• 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
McBryde KD, Kershaw DB, Smoyer WE. Curr Probl Pediatr 2001;31:275-307Niaudet P. Pediatric Nephrology,2004, p. 558-73
Supportive treatmentSupportive 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
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• 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;31:275-307Niaudet P. Pediatric Nephrology,2004, p. 558-73
Prednisone
SN inisial:a. ISKDC protocol (1970) or modification:
Prednisone full dose 60 mg/m2 BSA/d or 2mg/kgbw/d (max. 80 mg/d) 4 weeks.Followed prednisone 40 mg/m2BSA/d or 2/3 fulldose (1,5 mg/kgbw/d) for 4 weeks withintermitten dose (3 consecutive day) oralternating dose (alternate day in the morning)
Remission : 80% after prednisone 2 weeks94% after prednisone 4 weeks
Initial treatment : complete remission: 94% patients,relapse 60-70% and frequent relapse
50%
Corticosteroid
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Prednisone
SN inisial:a. ISKDC protocol (1970) or modification:
Prednisone full dose 60 mg/m2 BSA/d or 2mg/kgbw/d (max. 80 mg/d) 4 weeks.Followed prednisone 40 mg/m2BSA/d or 2/3 fulldose (1,5 mg/kgbw/d) for 4 weeks withintermitten dose (3 consecutive day) oralternating dose (alternate day in the morning)
Remission : 80% after prednisone 2 weeks94% after prednisone 4 weeks
Initial treatment : complete remission: 94% patients,relapse 60-70% and frequent relapse
50%
4 weeks 4 weeks
Remission(+)Proteinuria (-)Edema (-)
Alternating dose(AD)
Remission (-): Steroid resistant
Other immunosupressant
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Remission (-): Steroid resistant
Other immunosupressant
Prednisone FD: 60 mg/m2 BSA/day
Prednisone AD: 40 mg/m2 BSA/say
Fig: Initial treatment with corticosteroid
b. APN Jerman (1988):Prednisone 12 weeksu: FD 6 weeks and AD 6 weeksResults: - 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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b. APN Jerman (1988):Prednisone 12 weeksu: FD 6 weeks and AD 6 weeksResults: - 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
RECOMMENDED DOSAGESRECOMMENDED DOSAGESPrednisonePrednisone
DAILYDAILY : 60 mg/m: 60 mg/m22/day in 3 divided dose/day in 3 divided doseIntermittentIntermittent : 40 mg/m: 40 mg/m22/day in 3 divided dose,/day in 3 divided dose,
3 executive days in a week3 executive days in a weekAlternativelyAlternatively : 40 mg/m: 40 mg/m22/day single dose/day single dose
CyclophosphamideCyclophosphamide22--3 mg/kg/day for 83 mg/kg/day for 8 –– 12 weeks in combination with steroid12 weeks in combination with steroidintermittentintermittent
ChlorambucilChlorambucil
0,10,1--0,2 mg/kg/day in divided dose with steroid AD0,2 mg/kg/day in divided dose with steroid AD
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RECOMMENDED DOSAGESRECOMMENDED DOSAGESPrednisonePrednisone
DAILYDAILY : 60 mg/m: 60 mg/m22/day in 3 divided dose/day in 3 divided doseIntermittentIntermittent : 40 mg/m: 40 mg/m22/day in 3 divided dose,/day in 3 divided dose,
3 executive days in a week3 executive days in a weekAlternativelyAlternatively : 40 mg/m: 40 mg/m22/day single dose/day single dose
CyclophosphamideCyclophosphamide22--3 mg/kg/day for 83 mg/kg/day for 8 –– 12 weeks in combination with steroid12 weeks in combination with steroidintermittentintermittent
ChlorambucilChlorambucil
0,10,1--0,2 mg/kg/day in divided dose with steroid AD0,2 mg/kg/day in divided dose with steroid AD
Others ImmunosupressantOthers Immunosupressant• Cyclosporine• Mycophenolate Mofetil (MMF)• Tacrolimus• Mizoribine• Vincristine• Rituximab• Purine analog:
– Azatioprine– 6-merkaptopurin– 6-thioguanin
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• Cyclosporine• Mycophenolate Mofetil (MMF)• Tacrolimus• Mizoribine• Vincristine• Rituximab• Purine analog:
– Azatioprine– 6-merkaptopurin– 6-thioguanin
HospitalizationHospitalization
• NS with:- schock- anasarca oedema- severe hypertension- vomiting- renal failure- severe infection: peritonitis
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• NS with:- schock- anasarca oedema- severe hypertension- vomiting- renal failure- severe infection: peritonitis
ReferredReferred• 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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• 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
COMPLICATIONSCOMPLICATIONS
• Hypovolemia• Schock• Acute renal failure• Infections• Thrombosis• Electrolyte imbalance• Malnutrition• Delayed of growth
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• Hypovolemia• Schock• Acute renal failure• Infections• Thrombosis• Electrolyte imbalance• Malnutrition• Delayed of growth
THE CLINICAL RESPONS OF MINIMAL CHANGESTHE CLINICAL RESPONS OF MINIMAL CHANGESPATIENTS TO STEROID (ISKDC)PATIENTS TO STEROID (ISKDC)
Minimal Change 100%Minimal Change 100%
Responsive 93% Early Non responsive 7%
No-relaps36%
InfrequentRelapser
18%
FrequentRelapser39%
Non responsive
5%
Late responsive5%
Non-responsive2%
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No-relaps36%
InfrequentRelapser
18%
FrequentRelapser39%
Non responsive
5%
Late responsive5%
Non-responsive2%
(Kidney Int. 13-43, 1978)
PROGNOSISPROGNOSISPrognosis:
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: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
Prognosis …….Prognosis …….• Mortality
– 1940’s- 40% 1 year mortality– Nowadays 1-2%– Main causes
• Infection• Thrombosis
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• Mortality– 1940’s- 40% 1 year mortality– Nowadays 1-2%– Main causes
• Infection• Thrombosis
Thank you
Congenital Nephrotic SyndromeCongenital Nephrotic Syndrome
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
the majority of cases
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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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