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