Sindrom Nefrotik

pada Anak

dr. Jusli, M.Kes., SpA(K)

Divisi Nefrologi, Departemen Ilmu Kesehatan Anak
Fakultas Kedokteran Universitas Hasanuddin
Makassar, 11 April 2023
Pengapuh Nefrologi Anak

1. Prof Dr dr Syarifuddin Rauf, SpA(K)

2. dr Jusli, M.Kes., SpA(K)
Buku rujukan Sindrom Nefrotik pada Anak
1. Buku Ajar Nefrologi Anak UKK Nefrologi, IDAI, 2017
2. Buku Kompendium Nefrologi Anak, UKK Nefrologi IDAI,
2011
3. Buku Konsensus Sindrom Nefrotik pada Anak, UKK
Nefrologi IDAI, 2012
4. Buku Pediatric Nephrology On-The-Go, Edisi ke-4,
2021
• Tingkat 3
• Peserta didik mampu mendiagnosis, tata laksana
awal dan merujuk penyakit sindrom nefrotik
pada anak.
 DOKTER
SPESIALIS ANAK • DIAGNOSIS
• DIAGNOSIS • TERAPI
• Sindrom Nefrotik • DIAGNOSIS • SNI Kambuh sering,
• Kompetensi 3A • TERAPI dependen & Resisten
• SNI Serangan awal & Steroid, SN kongenital,
Kambuh awal dan SN+Komplikasi

KONSULTAN
DOKTER UMUM
NEFROLOGI
Standar Nasional Pendidikan Profesi Dokter Indonesia (SNPPDI). 2019, &
Standar Nasional Pendidikan Dokter Spesialis Anak, Kolegium Ilmu Kesehatan Anak
Indonesia, IDAI. 2018.

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• Menjelaskan definisi sindrom nefrotik
• Menjelaskan etiologi dan klasifikasi sindrom nefrotik
• Menjelaskan patogenesis dan patofisiologi sindrom nefrotik
• Menjelaskan gejala klinis dan laboratorium pasien sindrom nefrotik
• Menegakkan diagnosis dan diagnosis banding pasien sindrom
nefrotik
• Melakukan pengobatan pasien sindrom nefrotik
• Mengetahui dan mencegah komplikasi pasien sindrom nefrotik
• Menjelaskan prognosis sindrom nefrotik
• Sindrom Nefrotik adalah penyakit yang sering ditemukan pada
masa anak-anak.
• Sampai saat ini Terapi SN masih “Try and Error”.
• Insidens: 2 – 7 kasus baru per 100.000 anak dibawah 18 tahun
• Puncak insidens: 2 – 3 tahun
• Umur 1 – 4 thn 50%, < 10 thn 75%

(Roth KS el al. 2002., & Pasini A et al, 2017)

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 Richard Bright, 1829
Bright Disease
Edema-Proteinuria-Ginjal

Fredrich Von Muller, 1905

Nefritis - Nephrosis

Munk, 1913
Nephrosis Lipoid Henry Christian, 1929
Antibiotik 1940 • Klinik
• Laboratorium
Frasa “Nephrotic
Steroid sintetik1950 Syndrome”
Protokol ISKDC 1978, APN 1979, KDIGO 2012
• Proteinuria Masif
– > 40 mg/m2 /jam; 1 g/m2/24 jam
– > 50 mg/KgBB/hari
– Semikuantitatif (dipstik) > 3+
– Rasio Protein/kreatinin >2 (mg/mg)

• Hipoalbuminemia < 2,5 g/L

• Edema
• Hiperkolesterolemia > 250 mg/dl
 Sindrom Nefrotik

ETIOLOGI HISTOPATOLOGIS
Primer/Idiopatik Minimal
Sekunder Non-Minimal

RESPON TERHADAP PENGOBATAN

Responsif Steroid
Resisten Steroid
 SINDROM NEFROTIK

SN PRIMER SN SEKUNDER
95% (0-12 thn) 5% (0-12 tahun)

VASKULITIS/AUTOIM
SN IDIOPATIK SN GENETIK UN DISEASE
80-90% (2-8 thn) (Isolated atau syndromic)
INFEKSI
SN sensitif steroid SN Kongenital OBAT-OBATAN
95-100% < 3 Bln
DIABETES
SN resisten steroid SN Infatil
50-60% 4-12 Bln KANKER

(Pasini A et al. 2017)

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Prevalensi Kumulatif seluruh dunia 16 per 100.000 anak/tahun
Negara berkembang : 2 – 4 / 100.000 /tahun
India : 9 – 10 /100.000 (Arvind Bangga,RN Srivastava)
Indonesia : 6 / 100.000 Age < 14 tahun (Wila Wirya IGN)
RSUP.Dr.Wahidin Sudirohusodo 1-2 kasus baru/bulan
SN 15 kali lebih sering pada anak dibanding dewasa
Terutama anak < 5 tahun
Rasio ♂ : ♀ : 2 : 1
Mortality rates of 1 – 7,2% (sepsis & trombosis vaskuler)
1% SN 90% SN Primer/Idiopatik 10%
Kongenital/Infantil (ISKDC 1978) SN Sekunder
NPHS1 (nephrin) SN Kelainan minimal (76%) Nefritis lupus
FSGS (7%) HSP Nefritis
NPHS2 (Podocin)
MPGN (8%) Penyakit Autoimun
WT1
FGS (2%) Infeksi
LAMB2 Glomerulonefritis kronik (1%) Obat-obatan
PLCE1 Mesangeal proliferative Metabolik
LMX1B glomerulonefritis (4%)
Membranous nefropathy (2)
SN Herediter (alport
Syndrome

Mutasi genetik SN ±50

14
 Sel T dan B
IMMUNE
DYSREGULATION

MCD Hemopexin
FSGS Cardiotropin-like NPHS1 (nephrin)
NPHS2 (Podocin)
Cytokine 1 (CLC-1)
WT1
Soluble urokinase-type LAMB2
Plasminogen Activator MASSIVE PLCE1
Receptor (suPAR) PROTEINURIA LMX1B

SYSTEMIC PODOCYTE &

GLOMERULAR
CIRCULATING FILTRATION
FACTORS DEFFECT

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 Abnormalitas sistem imun

Disregulasi sel T

Release Limfokin

Efek pada MBG (hilangnya ion muatan negatif, ukuran pori-pori meningkat, swelling,
retraksi, effacement foot prosesus, dan detachement dair MBG

Proteinuria Masif

Hilangnya IgG, faktor B Hipoalbuminemia Hilangnya inhibitor koagulasi

Infeksi Edema Sintesa hepatik meningkat Hiperkoagulasi

Lipoprotein Prokoagulan

Hiperlipidemia (Saravanan et al. 2013., & Rauf S et al. 2002)

Gambar 1 Mekanisme dan Konsekuensi Proteinuria
19
PODOSIT

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 MEMBRAN FILTRASI GLOMERULUS

Glicoprotein,
podocalycin

(Heparin sulfate,proteoglycans, sialoproteins)

[Sialoprotein]
Lokasi dan Fungsi Mutasi
genetik berhubungan dengan
SNRS

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25
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27
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 Terminologi
• Respons
• Initial responder
• Initial non-responder
• Remisi
• Relaps
• Sindrom nefrotik relaps jarang (Infrequent relaps)
• Sindrom nefrotik relaps sering (Frequent relaps)
• Sindrom nefrotik kongenital
• Sindrom nefrotik infantil
• Sindrom nefrotik dependen steroid
• Sindrom nefrotik resisten steroid
• Sindrom nefrotik sensitif steroid.
 Manifestasi Klinis
Edema (40% BB), (palpebra, wajah, asites,
hidrotoraks,edema genital, edema ekstremitas)
Infeksi sekunder: kulit, peritonitis
Syok hipovolemia
Acute kidney injury
Trombosis vena
Tetani (hipocalcemia)
Anemia
Retardasi pertumbuhan
 Manifestasi klinis- Edema
• Patogenesis
– 80% Tekanan onkotik plasma di tentukan oleh
albumin
– Albumin < 2 g/dL : edema
– Deplesi volume intravaskuler
– Aktivasi sistem Renin-angiotensin-aldosteron
 PROTEINURIA MASIF

Hipoalbuminemia

Tekanan Onkotik intravaskular

menurun

Perpindahan cairan ke ekstravaskuler

Deplesi volume intravaskuler

Inhibisi ANP Aktivasi SNS Aktivasi RAAS sekresi ADH

Retensi Natrium dan Air

EDEMA
Teori underfill edema

Asupan Makan
Natrium dan air
 Sindrom Nefrotik

Peningkatan Resistensi ginjal terhadap ANP

reabsorbsi natrium &
air di tubulus distalis
Ekspansi volume intravaskular

Peningkatan tekanan hidrostatik intravaskuler

EDEMA

Teori Overfill edema Asupan garam dan air

 Striae abdominal dan Edema pitting

STRIAE EDEMA PRETIBIAL

edema pretibial
 EDEMA GENITAL

EDEMA SCROTUM

EDEMA VULVA
 PROTEINURIA
- Transferine â IgG â
- Glob.Thyroxin â Factor B â
- Glob. Vit. D â
- Antithrombin III â
HYPOALBUMINAEMIA

B-lipoprot ì ð hyperlipidaemia
ONCOTIC PRESSURE â
OEDEMA
HYPOVOLAEMIA
Circulation collaps
Hb ì Death
Aldosteron ì â
ò Packed cell vol ì Renal perfusion â
Na and H2O
retention ì Viscocity ì renin plasma ì Renal
ò failure
Trihono P, Simposium Nefrologi Anak, Makassar, 2006 Vein thrombosis
Makassar, 27 May 2006
Manifestasi klinis- Infeksi
• Infeksi bakteri
– Peritonitis, Sepsis
– Selulitis

• Infeksi virus
– Campak dapat menginduksi relaps SN
– Relaps sering karena infeksi virus
8 ETIOLOGI
o Konsentrasi IgG ↓
o Konsentrasi Faktor B ↓
o Gangguan opsonisasi
o Disfungsi limfosit.
 Manifestasi klinis- Trombosis
• Risiko trombosis á
– Fibrinogen á
– Faktor koangulasis V,VII,VIII,X á
– Antitrombin III â
– Hiperagregasi trombosit
– Viskositas darah ↑
– Trombositosis
Manifestasi klinis - Anemia

– Transferrin â
– Eritropoietin menurun
– Defisiensi Protein
– Infeksi
 Manifestasi klinis- Retardasi Pertumbuhan

• Retardasi Pertumbuhan
– Etiologi:
• IGF binding protein
– IGF I and II serum
– IF-receptor mRNA
• Pengobatan steroid
Urinalisis:
BJ é, pH é
proteinuria masif (selective - albumin 85-
95%)
leukosituria
hematuria (22,7% SNKM)
double refractile lipoid bodies
hyaline cast
• Plasma :
– Hb é, Hté
– hipoalbuminemia, rasio alb/glob terbalik
– hiperkolesterolemia:
• á LDL, VLDL, trigliserida and Lp(a)
– normal: ureum, kreatinin (á 33%)
– Imunoglobulin:
• IgG â, IgM á
• Sintesa kolesterol meningkat, trigliserida dan lipoprotein
• Katabolisme lipoprotein menurun

– Aktivasi lipoprotein lipase â

• Penurunan : aktivasi reseptor LDL
• Ekskresi HDL meningkat via urine
• Konsentrasi Lp(a) meningkat
1. Resisten steroid
2. Umur < 1 tahun
3. Umur > 10 tahun(dependen steroid atau resisten
steroid)
4. Hipertensi
5. Gross hematuria
6. Hipokomplementemia
7. Gagal ginjal
8. Riwayat keluarga gagal ginjal dan ketulian
DIAGNOSIS BANDING
• Protein losing enteropathy
• Hepatic failure
• GAGAL JANTUNG
• SINDROM NEFRITIK AKUT
• KWASHIORKOR

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1. Terapi imunosupresi
• Prednisone
• Levamizole
• Cyclophosphamide
• Cyclosporine A (CsA)
• Mycophenolate Mofetil (MPA)
• Tacrolimus
• Rituximab
2. Terapi non-imunosupresi
• Antiproteinuric agent
• Anti infection strategy
• Hiperlipidemia
• Trombosis
• Nutrsi
• Hipovolemia
• fungsi tiroid
 ISKDC 1978 APN 1979 KDIGO 2012
Daily Full Dose 60 mg/m2/day x 4 weeks 60 mg/m2/day x 6 weeks 60 mg/m2/day x 4-6 weeks
Alternate full dose 40 mg/m2/eod x 4 weeks 40 mg/m2/eod x 6 weeks 40 mg/m2/eod x 2-5 months
Tapering NA NA Tapering
Total cumulated dose 2240 mg/m2 3360 mg/m2 -
Total duration 8 weeks 12 weeks 3-6 months
Type of steroid Prednisolone Prednisolon Prednisolon
Maximum daily dosage 80 mg/day 80 mg/m2/day 60 mg/day

Sumber: Georges Deschenes et al. 2018 & KDIGO 2012, ISKDC The International study of
kidney disease in Children. APN Arbeitsgemeinschft fur Padiatrische Nephrologie. KDIGO
Kidney Disease Improving Global Outcome

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PREDNISONE
Indication :first episode of NS and
subsequent relapses
LEVAMIZOLE
Indication : Frequent relapsing or steroid
dependent NS with unacceptable steroid side-
effects, due to MCNS
CYCLOPHOSPHAMIDE
Indication : Frequent relapsing and steroid
dependent NS with unacceptable steroid side-
effects, due to MCNS
CYCLOSPORINE A (CSA)
Indication :
1. Steroid resistance and steroid dependent
patients with MCNS who has failed cytotoxic
therapy with alkylating agent such as
cyclophosphamide and with normal renal
function
2. NS due to FSGS with normal renal function
MYCOPHENOLATE MOFETIL (MPA)
Indication : Patients who are still relapsing while on
prednisone and CsA alternative drug in those
with CsA Toxicity
Tacrolimus
Indication : Patients who fail to respond within 2
months to CsA ± MPA therapy

Rituximab
Indication : Steroid dependent and steroid resistant
NS not responding well to conventional treatment.
1. ISKDC
CD = 4 weeks

AD/ID = 4 weeks
Tap. Off

1 2 3 4 5 6 7 8
remission remission
2. Arbeitsgemeinschaft fur Paediatrische Nephrologie (APN)
CD = 6 weeks

AD/ID = 6 weeks
Tap. off

1 2 3 4 5 6 7 8 9 10 11 12

remission remission
 CD

AD/ID
CD until remission Tap. Off
( 1 - 4 minggu )

1 2 3 4

remission remission
 Frequent Relapse Nephrotic Syndrome
or Steroid Dependent

Prednisone FD Remission
Prednisone AD + CPA
Decrease until treshoid doses
0.1 – 0.5 mg/kgBWAD
6-12 months

(1)
Relapse using Relapse using
Prednisone> 0.5 mg/kgBW AD Prednisone> 1 mg/kgBWAD
(2) or
Side effect ↑↑
Levamisol 2.5 mg/kgBW AD
(4-12 months) CPA 2-3 mg/kgBW
(3)
8-12 Weeks
 CPA

Relapse Prednisone standard

Relapse using Prednisone

> 0,5 mg/kgBW AD

Cyclosporine A 5 mg/kgBW/day
1 year

Treatment of Frequent relapses /steroid dependent Nephrotic Syndrome

 Supportive Care in Nephrotic Syndrome
• Management of Edema
• Management of Infection
• Management of Hypertension
• Management of Thrombosis
• Management of Hyperlipidemia
• Nutritional support
• Stress Dose of steroid
• Parent Education and Counseling
 Supportive Care in Nephrotic Syndrome

Control of Edema
1. Salt restriction
2. Albumin infusion 20% 1 g/kg over 4 hours followed by IV
furosemide 1-2 mg/kg mid-way and at end of infusion
3. Consider chronic diuretic therapy in patients with intractable
edema, using combination of:
• Furosemide 1-2 mg/kg
• Spironolactone
0-10 kg : 6,25 mg
11-20 kg : 12,5 mg
21-40 kg : 25 mg
> 40 kg : 25 mg 8H
• Bumetanide 25-50 mcg/kg (max 3 mg) daily, increasing to 8-
12H
Management of Edema in Nephrotic Syndrome
Evidence of hypovolemia
Yes
Normal saline,
Albumin infusion*
No

Oral furosemide 1-3 mg/kg/day

No response#

Add spironolactone 2-4 mg/kg/day

No response#

Increase furosemide to 4-6 mg/kg/day

No response#

Add hydrochlorthiazide 1-2 mg/kg/day or mitolazone 0,1 – 0,3 mg/kg/day

No response#

Furosemide IV bolus 1-3 mg/kg/dose or infusion 0,1 – 1 mg/kg/hour

No response#

20% albumin 1 g/kg followed by IV Furosemide

Supportive Care in Nephrotic Syndrome

Diet
1. Normal calorie, Low saturated fats (10-14% Protein,
40-45% poly- and mono-unsaturated fats, 40-50%
carbohydrate)
2. Salt restriction only if edema is present
3. Fluid restriction to 50% of maintenance if edema
present.
4. Protein requirements
High protein intake : no evidence of benefit unless
there is massive loss preventing growth
to avoid malnutrition, increase protein intake to
compensate for protein loss
 Age RDA Protein intake to compesate
(years) (g/kg/day) for protein loss (g/kg/d)
Infants 0-0.5 2.2 3.0-4.0
0.6-1.0 1.6 2.3-2.4
Children 1-3 1.2 1.9-2.0
4-6 1.2 1.9-2.0
7-10 1.0 1.7-1.8
Males 11-14 1.0 1.7-1.8
15-18 0.9 1.4-1.5
19-21 0.8 1.3
Females 11-14 1.0 1.7-1.8
15-18 0.8 1.4-1.5
19-21 0.8 1.3
Supportive Care in Nephrotic Syndrome

Decrease proteinuria
1. ACE Inhibitor :
Captopril 0,3 mg/kg/day 12H or 24H
Enalapril 0.1-1.0 mg/kg daily (maxi 40 mg daily)
Ramipril 0.05-0.2 mg/kg once daily (max 10 mg)

2. Angiotensin II Receptor Blocker :

Losartan 0,5-2 mg/kg daily (max 100 mg)
Supportive Care in Nephrotic Syndrome

Decrease Hypercholesterolemia
1. Dietary restriction
2. HMG CoA Reductase inhibitor :
Lovastatin 0.4-0.8 mg/kg nightly.dose can be increase
monthly. (max 40 mg 12H)

Atorvastatin 0.2-1.6 mg/kg nightly. Dose can be

increase monthly (max 80 mg nightly)

Simvistatin has the highest risk of rhabdomyolysis

Monitor liver function test and serum creatine kinase

monthly for first 3 months then 3-monthly
Supportive Care in Nephrotic Syndrome

Decrease hypercoagulopathy
1. Avoid hypovolemia
2. Aspirin 3-5 mg/kg (max 100 mg) daily or antiplatelet
agents such as dipyridamole 1-2 mg/kg (max 100 mg)
8H
3. Heparin dan warfarin (if there has been a thrombotic
event)
 Parent Education and Counseling
• Explained the natural history of the disease and
it’s outcome.
• Explained adverse effects high dose steroid
therapy and other medication.
• The patient should return for follow up at 4
weeks of therapy.
• The need to examine urine protein at home.
• A diary recording the protein excretion, intake of
medications and intercurrent illness.
KOMPLIKASI
• Infeksi
• Syok hipovolemia
• Acute kidney injury
• Penyakit ginjal kronik tahap akhir
• Steroid Toxicity
• Trombosis

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• Mortalitas
– Mortalitas 1940: 40% dalam 1 tahun
pertama
– Mortalitas saat ini 1-2%
– Penyebab utama kematian
• Infeksi
• Trombosis
• Penyakit ginjal kronik tahap akhir
– MCNS dalam 20 tahun: 4-5%
– GSFS dalam 5 tahun: 25%
PROGNOSIS
Idiopathic NS

Steroid sensitive (90%) Steroid resistant (10%)

Frequent relapses/S.dependent
(50%) ESRD
Infrequent relapses (33%)

No relapses (25%)
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 KESIMPULAN

1. SN pada anak bersifat idiopatik dan umumnya sensitif

kortikosteroid.
2. Trias sindrom nefrotik yaitu Proteinuria masif,
hipoalbuminemia dan edema.
3. Pengobatan SN pada anak sebaiknya dimulai dengan
prednison/ prednisolon full dose, dilanjutkan alternate day.
4. Selain terapi steroid, tata laksana SN harus diperhatikan
terapi penunjang.
TERIMA KASIH