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

DAMAGED

Proteinuria

Maintain barrier function

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

Pathogenesis of nephrotic syndrome

Filtration route

Restriction Molecules > 10 kDa

Electrostatic ( negative charge)

Disfunction
Non selective proteinuria Selective 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

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KOMPLIKASI Komplikasi Mayor

Infeksi Hipovolemia Trombosis GGA Hiperlipidemia Malnutrisi Loss of transport protein (transferrin, Hormonebinding 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 Hodgkins lymphoma Colon and bronchogenic carcinoma

Lain-lain
Infeksi virus DM Imunisasi

Edema anasarka

Ascites

Pretibial edema

Genital edema

Gambaran Histopatologi Sindrom Nefrotik pada Anak

Gambaran Histopatologi
Kelainan minimal (KM) Glomerulosklerosis fokal segmental (GSFS) Proliferatif mesangial difus (PMD) GN Membrano proliferatif (GNMB) Nefropati membranosa
ISKDC 1981 (N=471)
363 (77%)

Noer MS 1997 (n=71)

59 (83.1%)

Steroid Responsif (%) ISKDC

93.1

37 (7.8%)

7 (9.9%)

29.7

9 (1.9%)

3 (4.2%)

55.6

29 (6.2%)

6.9

6 (1.3%)

2 (2.8%)

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, 125136

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, its more permeable.

Benign looking on Light, capillaries are open, but appears thickened. This is immunecomplex 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

Histopathologic diagnosis of the NS

MANAGEMENT OF NEPHROTIC SYNDROME

1.

2. 3.

Drugs o Steroid o Non-steroid o Adjunctive therapy Levamisole ACE inhibitors, ARA Supportive treatment Management of complications

STANDARS TREATMENT OF NS CORTICOSTEROID (PREDNISON)

INITIAL
FULL DOSE 4 WEEKS ALTERNATING DOSE 4 WEEKS
Prednison FD: 60 mg/m2/day Prednison AD: 40 mg/m2/day

REMISSION (+)

REMISSION (-)

STEROID 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 Hb > 8 g/dL; Leucocyte >5,000/L; platelet >100,000/L

Prerequisite:

Contraindication of Steroid/ Toxic steroid

Contraindication steroid:

Severe hypertension Renal failure Severe infection Diabetes mellitus, etc

Severe hypertension Massive striae Cataract. etc

Toxic steroid

CPA oral or pulse Others: Chlorambucil Cyclosporin

STEROID RESISTANT NEPHROTIC SYNDROME

RESISTANT TO: - Alkylating agents - Cyclosprorin (or can not effort)

Combination ACE INHIBITOR + ARB to reduce urinary TGF-1 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-1 reduce risk of renal sclerosis

Supportive treatment

General

Bed rest Mantoux test Elimination of focus infection: teeth, ears, worms Generalized edema (severe) Hypovolaemia Severe infection: peritonitis Renal failure

Indication for admission

Treatment- Diet

Protein normal 2-2,5 g/kg/day

Low protein

Decreases albuminuria Malnutrition

High protein: hyperfiltration glomerulosclerosis During edema Steroids

Salt restriction

Calorie control

DIURETIC

Furosemide 1-3 mg/kg + spironolacton 2-4 mg/kg

Admitted

no respond (no weight loss or diuresis in 48 hours)

Double dose of furosemide untill diuresis 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

Indications

Stress the glomerulus scarring

Hypovolemia

Abdominal pain

Hypotension
Oliguria Renal failure

Progressive glomerulosclerosis Increase the time to achieve remission

Shock

Severe Infection

Time to response to steroids in SSINS: Australian data 2002

100 80 60 40 20 0 1 2 3 4 5 6 7 8

Median time to response = 10 days

Week of response

Outcome at 1 year in children with Steroid sensitive NS

Steroid dependent No relapse

17%
Frequent relapse

21%

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 !