SINDROM

NEFROTIK
PADA ANAK

BOBBY SETIADI DHARMAWAN

 Sindrom Nefrotik
GEJALA KLINIK
 Edema (40% berat badan), asites
 Gejala infeksi sekunder
LABORATORIUM
 Proteinuria (10-15 mg/hari)
 Diuresis << BJ urin >>
 Sedimen urin: silinder hialin, granular
 Kimia darah : hipoalbuminemia, Hiperlipidemia
 Proteinuria Masif
 40 mg/m2/jam urine
 Protein/kreatinin ratio > 2 mg/mg
 Dipstick ≥ +2)

Hipoalbuminemia < 2,5 g/dL

Edema anasarka

Hiperlipidemia
Pathogenesis of nephrotic syndrome

Maintain
DAMAGED barrier
Proteinuria
function

McBryde KD. Pediatric steroid-resistant nephrotic syndrome. Curr Probl Pediatr.2001;31:275-307

 Pathogenesis of nephrotic syndrome

Filtration route

Restriction Electrostatic
Molecules > 10 kDa ( negative charge)

Disfunction
Non selective Selective
proteinuria proteinuria

Haycock G. The child with idiopathic nephrotic syndrome. In: Postlethwaite R, editor. Clinical
paediatric nephrology. 3rd edition. Baltimore: Oxford University Press;2003. p. 344-7.
 Sindrom Nefrotik

ETIOLOGI
 Diopatik (SNI) 90%
 Kongenital ( 0-3 bulan)
 Sekunder : mengikuti penyakit sistemik
 Sindrom Nefrotik
SN BAWAAN
 Finnish type
 Jarang
 Plasenta besar
 Autosomal resesif
 Edema masa neonatus sampai 3 bulan
 Mutasi gen NPHS1, lokasi pada kromosom 19q13.1
 Resisten obat
SN SEKUNDER
 Penyakit metabolik : Diabetes, amiloidosis
 Penyakit infeksi : Malaria, hepatitis B, sistosoma
 Toksin dan alergen : Logam berat, gigitan serangga
 Penyakit sistemik : SLE, PHS, poliarteritis
 Neoplasma : Hodgkin, tumor paru
 Sindrom Nefrotik
BATASAN
 Remisi: proteinuria (-) / trace 3 hari
berturut-turut (1 minggu)
 Relaps: proteinuria > +2 dlm 3 hari
berturut-turut (1 minggu)
 Relaps jarang : Relaps < 2x/6 bulan
pertama setelah respon awal atau <
4x/tahun pengamatan
 Relaps sering : Relaps > 2x/6 bulan
pertama setelah respon awal atau >
4x/tahun pengamatan
 Sindrom Nefrotik
BATASAN
 Dependen steroid: Relaps 2x berurutan
saat dosis steroid diturunkan atau 14 hr
terapi dihentikan
 Resisten steroid : tidak terjadi remisi pada
terapi prednison full dose 4 minggu
 Sensitif steroid : Remisi terjadi pada
pemberian prednison full dose dalam 4
minggu
 Sindrom Nefrotik
KOMPLIKASI
 Komplikasi Mayor
 Infeksi
 Hipovolemia
 Trombosis
 GGA
 Hiperlipidemia
 Malnutrisi
 Loss of transport protein (transferrin, Hormone-
binding protein)
 Efek samping pengobatan
 Steroid
 Alkylating agent
 Cyclosporin, etc
 Sindrom Nefrotik
KONDISI YANG BERHUBUNGAN DENGAN SN
 Alergi
 Jamur
 Susu sapi
 Sengatan lebah
 House dust
 Obat-obatan
 AINS
 Ampisilin
 Merkuri
 Keganasan
 Penyakit Hodgkin dan Non Hodgkin’s lymphoma
 Colon and bronchogenic carcinoma
 Lain-lain
 Infeksi virus
 DM
 Imunisasi
Edema anasarka
Ascites
Pretibial edema
Genital edema
 Gambaran Histopatologi Sindrom
Nefrotik pada Anak
ISKDC Noer MS Steroid
Gambaran Histopatologi 1981 1997 Responsif
(N=471) (n=71) (%) ISKDC
Kelainan minimal (KM) 363 (77%) 59 (83.1%) 93.1

Glomerulosklerosis fokal segmental 37 (7.8%) 7 (9.9%) 29.7

(GSFS)

Proliferatif mesangial difus (PMD) 9 (1.9%) 3 (4.2%) 55.6

GN Membrano proliferatif (GNMB) 29 (6.2%) - 6.9

Nefropati membranosa 6 (1.3%) 2 (2.8%) 0

Epidemiologi
 Gambaran Histopatologi
Sindrom Nefrotik pada Anak

Normal

MCNS

Cross-sections of the glomerular capillary wall in a non-proteinuric patient (A and B) and in a

patient with MCNS (C and D) as revealed by electron microscopy. cell bodies of podocytes
(P) extend into the urinary space, while their foot processes attach to the GBM.
In normal individuals, foot processes are arranged in a regular interdigitating pattern (B) with
interconnecting slit diaphragms (small arrows).

Van den Berg, Weening, Clinical Science (2004) 107, 125–136

 Light microscopy of the MCNS

MCD has no glomerular lesions by light microscopy.

the thickness of the glomerular capillary walls is normal, the thickness of the glomerular capillary
wall (long arrow) is similar to that of the tubular basement membranes
and there is neither expansion nor hypercellularity in the mesangial areas in the central or stalk
regions of the tuft (arrows). Courtesy of Helmut G Rennke.
 Immunofluorescence Microscopy

Shows no staining with antisera specific for IgG, IgA, IgM, C3, C4, or C1q. Absence of humoral
components of the immune system

There are occasional specimens that will have small amounts of exclusively mesangial
immunoglobulin (especially IgM) or complement accumulation that can still be designated minimal
change glomerulopathy. A little bit of mesangial IgM and/or C3 without ultrastructural evidence for
electron dense deposits is tolerable for a diagnosis of minimal change glomerulopathy.

Well defined mesangial electron dense deposits, however, worsen the prognosis for response to
steroids or spontaneous remission. Thus, if there are electron dense deposits, minimal change
glomerulopathy is not an appropriate diagnoses.
 Electron Microscopy

Characteristic histologic finding in MCD is diffuse effacement of the epithelial ceel foot proces on EM.
A finding also observed with FGS
Electron micrograph in minimal change disease showing a normal glomerular basement membrane
(GBM), no immune deposits, and the characteristic widespread fusion of the epithelial cell foot
processes (arrows). Courtesy of Helmut Rennke, MD.
Histopathologic diagnosis of the NS
Histopathologic diagnosis of the NS
MGN by Light has a thickening of the capillary wall, sort of referred to as menbrane
of the capillary. Its parodoxical, you would think w/ thicker membrane, you should
have less protein getting across. But the fact is there more proteinuria, b/s abnormal
permeability. Even though the basementmembrane is thicker, it’s more permeable.
 Histopathologic diagnosis of the NS
Benign looking on Light, capillaries are open, but appears thickened. This is immune-
complex mediated dz. Immune-complex deposit along the capillary loops. By IF, we can
see very bright staining that is indicating the location of immune complex
MANAGEMENT OF NEPHROTIC
SYNDROME
1. Drugs
o Steroid
o Non-steroid
o Adjunctive therapy
 Levamisole

 ACE inhibitors, ARA

2. Supportive treatment
3. Management of complications
 STANDARS TREATMENT OF NS
CORTICOSTEROID (PREDNISON)

INITIAL
FULL DOSE ALTERNATING DOSE

4 WEEKS 4 WEEKS
Prednison FD: 60 mg/m2/day
Prednison AD: 40 mg/m2/day

REMISSION (+) STEROID

REMISSION (-)
SENSITIVE

STEROID RESISTANT

IMMUNOSUPPRESIVE AGENTS
Steroid Resistant Nephrotic Syndrome
 Cyclophosphamide
 Oral: 2-3 mg/kg/day, divided dose
 For 8 -12 weeks
 Pulse:
 500-750 mg/m2 BSA diluted in 250 ml NaCl
0.9% in 2 hours
 Prerequisite:
 Hb > 8 g/dL; Leucocyte >5,000/L;
platelet >100,000/L
Contraindication of Steroid/ Toxic
steroid
 Contraindication steroid:
 Severe hypertension
 Renal failure
 Severe infection CPA oral or pulse
 Diabetes mellitus, etc  Others:
Chlorambucil
 Toxic steroid Cyclosporin
 Severe hypertension
 Massive striae
 Cataract. etc
STEROID RESISTANT NEPHROTIC SYNDROME

RESISTANT TO: - Alkylating agents

- Cyclosprorin (or can not effort)

Combination ACE INHIBITOR + ARB

to reduce urinary TGF-β1 excretion

 slow progression to renal failure (RENOPROTECTIVE)

 Captopril 0.3 mg/kg/dose, 3 x a day
Lisinopril 0.1 mg/kg/dose, single dose
Losartan 0.75 mg/kg/dose, single dose
 Theories Why ACE Inhibitors
Might Work
 Lower arterial blood pressure
 Lower intraglomerular pressure by effects
of efferent arteriole
 Change permeability characteristics at the
level of the glomerulus
 Reduce urinary TGF-β1 reduce risk of
renal sclerosis
 Supportive treatment
 General
 Bed rest
 Mantoux test
 Elimination of focus infection: teeth, ears, worms
 Indication for admission
 Generalized edema (severe)
 Hypovolaemia
 Severe infection: peritonitis
 Renal failure
 Treatment- Diet
 Protein normal 2-2,5 g/kg/day
 Low protein
 Decreases albuminuria
 Malnutrition
 High protein: hyperfiltration  glomerulosclerosis
 Salt restriction
 During edema
 Calorie control
 Steroids
 DIURETIC
Furosemide 1-3 mg/kg
+ spironolacton 2-4 mg/kg
no respond (no weight loss or diuresis in 48 hours)

Double dose of furosemide untill diuresis Admitted

Max. 4-5 mg/kg/day

Add metamizol 0,1-0,3 mg/kg/day or HCT 1-4 mg/kg

Furosemide IV bolus 1-3 mg/kg/dose

or per drip 0,1-1 mg/kg per hour

Albumin 20% 1g/kg followed by IV furosemid

Source: Indian Pediatrics 2001;39:975

 Treatment - Albumin
 Controversial Stress the glomerulus
 Indications   scarring
 Hypovolemia
 Abdominal pain  Progressive
 Hypotension glomerulosclerosis
 Oliguria
 Renal failure  Increase the time to
 Shock achieve remission
 Severe Infection
 Time to response to steroids in
SSINS: Australian data 2002
100
Cumulative remission %

80

60

Median time to
40
response = 10 days
20

0
1 2 3 4 5 6 7 8

Week of response
 Outcome at 1 year in children with
Steroid sensitive NS
Steroid
dependent No relapse

17% 21%

Frequent
relapse 22%

40% Infrequent
relapse

• STEROID RESISTANT NS: 20%

Prognosis

Adulthood relapser

Adulthood non relapser

 Sindrom Nefrotik
INDIKASI BIOPSI
 Pada Presentasi awal
 Awitan SN pada usia <1thn atau >16 thn
 Hematuria nyata/mikroskopik persisten, kadar
C3 rendah
 Hipertensi menetap
 Penurunan fungsi ginjal bukan karena
hipovolemi
 Tersangka SN sekunder
 Setelah Pengobatan inisial
 SN Resisten Steroid, relaps sering
 Sebelum terapi Siklosporin
 When to Refer?
 Reason for referral
 Diagnostic: FSGS, secondary NS
 Adverse effect of steroid / cytostatic
 Renal biopsy

 Cases to be referred
 Resistant steroid
 Infantile NS
 Hypocomplementemia persistent
 Mixed nephrotic dan nephritic
 Severe complications
 Dependent steroid, frequent relapses
THANK YOU !