NEPHROTIC SYNDROME NEPHROTIC SYNDROME DJOKO WIBISONO DJOKO WIBISONO 14 – Maret - 2011 14 – Maret - 2011
NEPHROTIC NEPHROTIC SYNDROMESYNDROME
DJOKO WIBISONODJOKO WIBISONO14 – Maret - 201114 – Maret - 2011
Glomerulus: “capillary network” produce ultrafiltrate
Glomerular filtration rate:
- GBF
- ultrafiltration pressure- Surface area mesangail cell contractility
Glomerular endothelium: antithrombotic & antiadhesive
Glomerular filtration barrier: Physicochemical & electrostatic charge
Arterial tone
Glomerulus
NO, ET, Prostacyclin
Anatomy of the GlomerulusGlomerular capsule
Capillary lumen
Mesangial cell
GBM
Mesangial matrix
Endothelial cell
Visceral epithelial cell
Parietal epithelial cell
Primary Glomerular Diseases Nephrotic presentation (nephrotic
syndrome)– Minimal change disease (MCD)– Focal segmental glomerulosclerosis
(FSGS)– Membranous GN– Membranoproliferative GN
Acute nephritis (nephritic syndrome)– Acute proliferative GN– Crescentic glomerulonephritis (RPGN)– Anti-GBM Disease
Primary hematuria– IgA Nephropathy
Glomerulonephritis
Broad category of glomerular disease manifesting as cellular proliferation and inflammation of glomeruli.
Acute or chronic, Primary and secondary, Majority are immune mediated.
Thought to be the case particularly because: (1) 25% (high) of CO received by kidneys, (2) High hydrostatic pressures at glomerular capillaries, (3) Highly fenestrated glomerular endothelium which
maximizes contact between immune reactants & GBM (4) Sieving effect of glomerular filter which concentrates
injurious agents.
General clinical syndrome in patients with glomerulonephritis
1. Asymptomatic/persistent hematuria and/or proteinuria
2. Acute glomerulonephritis 3. RPGN, acute renal failure
4.4. Nephrotic syndromeNephrotic syndrome
5.5. Chronic glomerulonephritisChronic glomerulonephritis
PATHOGENESIS OF GLOMERULAR INJURY
Clinicopathologic Correlates in Glomerular Disease
Clinicopathologic: induced by a variety of difference Clinicopathologic: induced by a variety of difference
pathogenic mechanism pathogenic mechanism prompt diagnosis, optimal prompt diagnosis, optimal
management and accurate prognostic management and accurate prognostic requires: requires:
1. Recognition of the presenting syndrome1. Recognition of the presenting syndrome
2. Delineated of the underlying morphologic pattern2. Delineated of the underlying morphologic pattern
3. Elucidation of the specific renal limited or 3. Elucidation of the specific renal limited or
systemicsystemic
disease. disease.
Nomenclature
GlomerulonephritisGlomerulonephritis ≈≈ glomerulopathyglomerulopathy glomerular injury glomerular injury Glomerulonephritis:Glomerulonephritis: injury with evidence of inflammation injury with evidence of inflammation
such as leukocyte infiltration, antibody deposition, and/or such as leukocyte infiltration, antibody deposition, and/or complement activation. complement activation.
PrimaryPrimary or secondary or secondary acuteacute (days or weeks), (days or weeks), subacutesubacute or or rapidly progressive rapidly progressive
((weeks or a few months), and weeks or a few months), and chronicchronic (many months or (many months or years) years)
FocalFocal (<50%) or (<50%) or diffusediffuse ( (>>50%) of glomeruli. 50%) of glomeruli. SegmentalSegmental (involve part) or (involve part) or globalglobal (almost all) of the (almost all) of the
glomerular tuft. glomerular tuft.
Nomenclature (cont)
ProliferativeProliferative : : ↑↑ glomerular cell number glomerular cell number due to due to infiltration or proliferation. infiltration or proliferation.
IntracapillaryIntracapillary or or endocapillary: endocapillary: endothelial or endothelial or mesangial cells and mesangial cells and extracapillary: extracapillary: cells in Bowman's cells in Bowman's space space
RPGNRPGN ≈≈ crescentic glomerulonephritiscrescentic glomerulonephritis Membranous: Membranous: dominated by expansion of the GBM by dominated by expansion of the GBM by
immune deposits immune deposits Sclerosis: Sclerosis: ↑↑ amount of homogeneous nonfibrillar amount of homogeneous nonfibrillar
extracellular material of the same ultrastructural and extracellular material of the same ultrastructural and chemical composition as GBM and mesangial matrix.chemical composition as GBM and mesangial matrix.
FibrosisFibrosis: consequence of healing of crescents : consequence of healing of crescents (deposition of collagens type I and III) (deposition of collagens type I and III)
Nephrotic SyndromeNephrotic Syndrome
Is not a disease but a group of Is not a disease but a group of signs and symptoms seen in signs and symptoms seen in patients with heavy proteinuriapatients with heavy proteinuria
presents with oedemapresents with oedema proteinuria usually > 3.5g / 24hrs proteinuria usually > 3.5g / 24hrs
(>0.05g / kg / 24hrs in children)(>0.05g / kg / 24hrs in children) serum albumin < 30g/lserum albumin < 30g/l other features: hyperlipidaemia, other features: hyperlipidaemia,
and hypercoaguable stateand hypercoaguable state
PathophysiologyPathophysiology proteinuria: due to an increase in proteinuria: due to an increase in
glomerular permeabilityglomerular permeability hypoalbuminuria: occurs when liver hypoalbuminuria: occurs when liver
synthesis cannot keep up with urine lossessynthesis cannot keep up with urine lossesoedema mechanism is complex and still in oedema mechanism is complex and still in
dispute: primary dispute: primary salt and water retentionsalt and water retention associated with reduced renal function as well associated with reduced renal function as well as as reduced plasma oncotic pressurereduced plasma oncotic pressure are primary are primary factors (factors (overfill and underfilloverfill and underfill))
minimal change disease fits the underfill theory minimal change disease fits the underfill theory bestbest
hyperlipidaemia: increased liver synthesishyperlipidaemia: increased liver synthesis hypercoagulation: increased fibrinogen hypercoagulation: increased fibrinogen
and loss of antithrombin IIIand loss of antithrombin III
Primary glomerular diseases Primary glomerular diseases commonly causing the nephrotic commonly causing the nephrotic syndromesyndrome minimal change diseaseminimal change disease focal and segmental glomerulosclerosisfocal and segmental glomerulosclerosis membranous glomerulonephritismembranous glomerulonephritis proliferative glomerulonephritis proliferative glomerulonephritis
(various histology and less common (various histology and less common cause)cause)membranoproliferative (mesangiocapillary)membranoproliferative (mesangiocapillary) focal proliferativefocal proliferativediffuse proliferativediffuse proliferativemesangial proliferative mesangial proliferative
Other causes of the nephrotic Other causes of the nephrotic syndrome 1syndrome 1
Systemic diseasesSystemic diseasesdiabetes mellitusdiabetes mellitusamyloidosisamyloidosisSLE and other connective tissue diseasesSLE and other connective tissue diseasesHIV/AidsHIV/Aids,HBV,HCV,HBV,HCV
nephrotoxinsnephrotoxinsnsaidsnsaidsmercury poisoningmercury poisoningpenicillaminepenicillaminegold saltsgold salts
Other causes of the nephrotic Other causes of the nephrotic syndrome 2syndrome 2
AllergiesAllergies bee stingbee sting pollenspollens poison ivypoison ivy
Circulatory effectsCirculatory effects congestive cardiac failurecongestive cardiac failure constrictive pericarditisconstrictive pericarditis renal vein thrombosis (cause or result?)renal vein thrombosis (cause or result?)
NeoplasticNeoplastic leukaemialeukaemia solid tumourssolid tumours
Nephrotic syndromeNephrotic syndrome
The above causes result in The above causes result in glomerular proteinuriaglomerular proteinuria
Heavy urinary loss of proteins, Heavy urinary loss of proteins, including albumin, results in including albumin, results in hypoalbuminaemiahypoalbuminaemia
Nephrotic syndromeNephrotic syndrome
Reduced blood albumin level results Reduced blood albumin level results in decreased intravascular oncotic in decreased intravascular oncotic pressure, thus pressure, thus edemaedema develops develops
Loss of fluid from the intravascular Loss of fluid from the intravascular compartment, causes activation of compartment, causes activation of RAS, which stimulates salt and RAS, which stimulates salt and water retention and thus, worsens water retention and thus, worsens the oedemathe oedema
Nephrotic syndromeNephrotic syndrome
Most proteins are lost to the Most proteins are lost to the urine, except the very large urine, except the very large proteins, e.g. lipoproteinproteins, e.g. lipoprotein
Due to hypoproteinaemia, the Due to hypoproteinaemia, the liver increases rate of protein liver increases rate of protein synthesissynthesis
Nephrotic syndromeNephrotic syndrome
For most proteins, the increased For most proteins, the increased hepatic synthesis cannot fully hepatic synthesis cannot fully compensate for the severe urine losscompensate for the severe urine loss
But for lipoproteins, since it is But for lipoproteins, since it is retained and in addition to the retained and in addition to the increased hepatic synthesis, increased hepatic synthesis, hyperlipoproteinaemiahyperlipoproteinaemia results results
Nephrotic syndromeNephrotic syndrome
As for the loss of other proteins, As for the loss of other proteins, there is there is loss of anti-coagulantsloss of anti-coagulants such as such as antithrombin IIIantithrombin III, and thus , and thus nephrotic syndrome could be nephrotic syndrome could be complicated by thromboembolic complicated by thromboembolic disorders, such as renal vein disorders, such as renal vein thrombosisthrombosis There is also loss of immunoglobulins, There is also loss of immunoglobulins,
and thus, immunodeficiency of IgG and thus, immunodeficiency of IgG may resultmay result
Clinical Features- Clinical Features- EdemaEdema
Physical examPhysical exam– Accumulates in gravity dependent Accumulates in gravity dependent
tissuestissues– Puffiness around eyesPuffiness around eyes– Genital edema is generally painfulGenital edema is generally painful
Muehrcke's bands in nephrotic syndrome. The white Muehrcke's bands in nephrotic syndrome. The white band grew during a transient period of band grew during a transient period of hypoalbuminemia caused by the nephrotic syndrome. hypoalbuminemia caused by the nephrotic syndrome.
Xanthelasma in nephrotic syndrome. These prominent Xanthelasma in nephrotic syndrome. These prominent xanthelasma developed within a period of two months xanthelasma developed within a period of two months in a patient with recent onset of severe nephrotic in a patient with recent onset of severe nephrotic syndrome and serum cholesterol 550 mg/dL (14.2 syndrome and serum cholesterol 550 mg/dL (14.2 mmol/L) mmol/L)
Clinical Features- Clinical Features- EdemaEdema PathogenesisPathogenesis
– 80% of oncotic pressure due to 80% of oncotic pressure due to albuminalbumin
– Below 2 g/dL edema accumulatesBelow 2 g/dL edema accumulates– Intravascular volume depletionIntravascular volume depletion– Renin-aldosterone activationRenin-aldosterone activation
Clinical Features- Clinical Features- InfectionInfection Bacterial infectionsBacterial infections
– Prone to bacterial sepsis Prone to bacterial sepsis – CellulitisCellulitis– IgG levels lowIgG levels low– Factor B levels lowFactor B levels low– Lymphocyte function impairedLymphocyte function impaired
Viral InfectionsViral Infections– Measles may induce remission in NSMeasles may induce remission in NS– Relapse preceded by viral infectionRelapse preceded by viral infection
Clinical Features- Clinical Features- ThrombosisThrombosis Serious risk of thrombosisSerious risk of thrombosis Increased fibrinogen concentrationIncreased fibrinogen concentration Antithrombin III concentration Antithrombin III concentration
reducedreduced NS patients resistant to heparinNS patients resistant to heparin Platelets hyperaggregablePlatelets hyperaggregable Increased blood viscosityIncreased blood viscosity
Investigation of Investigation of Nephrotic syndromeNephrotic syndrome Serum electrolytes, protein and lipid Serum electrolytes, protein and lipid
profileprofile Serum urea and creatinineSerum urea and creatinine 24hr urine protein excretion24hr urine protein excretion Creatinine clearanceCreatinine clearance Urine microscopyUrine microscopy Renal biopsyRenal biopsy Investigation for systemic illnessInvestigation for systemic illness
Laboratory FeaturesLaboratory Features
Hct may be elevatedHct may be elevated Hyponatremia is commonHyponatremia is common Plasma creatinine is elevated in Plasma creatinine is elevated in
33% of patients33% of patients
Laboratory- Plasma Laboratory- Plasma ProteinProtein AlbuminAlbumin
– Hypoalbuminemia due to loss via the Hypoalbuminemia due to loss via the kidneykidney
Urinary excretionUrinary excretion Proximal tubular cells catabolismProximal tubular cells catabolism
ImmunoglobulinsImmunoglobulins– IgG levels reducedIgG levels reduced– IgM levels elevatedIgM levels elevated– IgM-IgG-SwitchingIgM-IgG-Switching
Laboratory- Laboratory- HyperlipidemiaHyperlipidemia Increased synthesis of cholesterol, Increased synthesis of cholesterol,
triglycerides and lipoproteinstriglycerides and lipoproteins Decreased catabolism of Decreased catabolism of
lipoproteinslipoproteins– Decreased activity of lipoprotein lipaseDecreased activity of lipoprotein lipase
Decreased LDL receptor activityDecreased LDL receptor activity Increased urinary loss of HDLIncreased urinary loss of HDL LpLp(a) (a) levels are elevatedlevels are elevated
Laboratory- UrinalysisLaboratory- Urinalysis
Broad, waxy castsBroad, waxy casts Lipid dropletsLipid droplets Hematuria 22.7% of MCNS Hematuria 22.7% of MCNS Low urine sodiumLow urine sodium High osomolalityHigh osomolality
Investigation of Investigation of Nephrotic syndromeNephrotic syndrome
Exception to renal biopsy:Exception to renal biopsy:– Children presenting with nephrotic Children presenting with nephrotic
syndrome are most commonly due to syndrome are most commonly due to minimal change diseaseminimal change disease
– Readily responds to steroidReadily responds to steroid– Therefore, give empirical steroid Therefore, give empirical steroid
treatmenttreatment– Preform renal biopsy when no Preform renal biopsy when no
reponse to steroid treatmentreponse to steroid treatment
Indications for BiopsyIndications for Biopsy
PretreatmentPretreatment– RecommendedRecommended
Onset age < 6 monthsOnset age < 6 months Macroscopic hematuriaMacroscopic hematuria Microscopic hematuria and HTNMicroscopic hematuria and HTN Low C3Low C3 Renal failureRenal failure
– DiscretionaryDiscretionary Onset between 6-12 months or > 12 yearsOnset between 6-12 months or > 12 years Persistent HTN of hematuriaPersistent HTN of hematuria
Indications for BiopsyIndications for Biopsy
Post treatmentPost treatment– Steroid resistanceSteroid resistance– Frequent relapsersFrequent relapsers
Nephrotic syndrome biopsy histology in adults Nephrotic syndrome biopsy histology in adults at different agesat different ages
Management of the nephrotic Management of the nephrotic syndromesyndrome
Na+< 60 mmol/24 hrsNa+< 60 mmol/24 hrs water restrictionwater restriction diuretics (if not volume depleted)diuretics (if not volume depleted) reduced protein diet (controversial)reduced protein diet (controversial) treat infectionstreat infections prophylaxis for thrombosisprophylaxis for thrombosis specific therapyspecific therapy
corticosteroidscorticosteroids immunosuppressionimmunosuppression
Specific treatmentsSpecific treatments
Minimal change diseaseMinimal change diseaseprednisone for 16 weeks (p)prednisone for 16 weeks (p)prednisone and cyclophosphamide ( p+c)prednisone and cyclophosphamide ( p+c)
FSGSFSGSp, p+c, p+cyclosporine(cs)p, p+c, p+cyclosporine(cs)
MembranousMembranousPonticelli RegimenPonticelli Regimenp+cp+c
Type of medicines:Type of medicines:
• Diuretik loopDiuretik loop• KortikosteroidKortikosteroid• AzatioprinAzatioprin• KlorambusilKlorambusil• SiklofosfamidSiklofosfamid• Siklosporin-ASiklosporin-A• Mikofenolat mofetilMikofenolat mofetil
Management of the Management of the nephrotic syndromenephrotic syndrome
Therapy for edemaTherapy for edema• Furosemid i.v. : 0,1 – 0,4 mg/kg Furosemid i.v. : 0,1 – 0,4 mg/kg
BW/hr in NaCl 0,9% or Dext 5% BW/hr in NaCl 0,9% or Dext 5% solutionsolution
• Furosemid 6O mg in 200 ml Furosemid 6O mg in 200 ml Albumin 20% (effective for Albumin 20% (effective for plasma albumin : <2 g/dl)plasma albumin : <2 g/dl)
Management of the Management of the nephrotic syndromenephrotic syndrome
Pengobatan dengan Pengobatan dengan imunosupresanimunosupresan Steroid (obat utama dan tetap ada Steroid (obat utama dan tetap ada
dalam setiap rejimen)dalam setiap rejimen) Bentuk rejimen dan lama pengobatan Bentuk rejimen dan lama pengobatan
berbeda untuk setiap kelainan berbeda untuk setiap kelainan histologik yang mendasari SNhistologik yang mendasari SN
SN merupakan manifestasi klinik dari SN merupakan manifestasi klinik dari GN primer yang dibagi dalam dua GN primer yang dibagi dalam dua kelompok besar:kelompok besar:
1.1.Inflamasi: GNMP, GNMsP, GN kresentiInflamasi: GNMP, GNMsP, GN kresenti
2.2.Non inflamasi: kelainan minimal, GNFS, Non inflamasi: kelainan minimal, GNFS, nefropati membranosa (epitel) nefropati membranosa (epitel)
Kelainan minimalKelainan minimal1.1. Prednison 60 mg/mPrednison 60 mg/m22 (maks 80 mg) selama (maks 80 mg) selama
4-6 minggu4-6 minggu2.2. Setelah 4-6 minggu prednison 40 mg/mSetelah 4-6 minggu prednison 40 mg/m22
selang sehari selama 4-6 mingguselang sehari selama 4-6 minggu3.3. Dalam pemberian prednison dapat terjadi:Dalam pemberian prednison dapat terjadi:
a.a. Relaps: prednison kembali 60 mg/mRelaps: prednison kembali 60 mg/m22 (maks 80 mg) setiap hari sampai 3 hari (maks 80 mg) setiap hari sampai 3 hari bebas protein dalam urine kemudian bebas protein dalam urine kemudian kembali selang sehari 40 mg/m2 selama kembali selang sehari 40 mg/m2 selama 4 minggu. Bila sering relaps ditambah 4 minggu. Bila sering relaps ditambah siklofosfamid 2 mg/kgBB atau klorambusil siklofosfamid 2 mg/kgBB atau klorambusil 0,15mg/kgBB selama 8 minggu. Bila 0,15mg/kgBB selama 8 minggu. Bila gagal diberi siklosporin 5 mg/kgBB gagal diberi siklosporin 5 mg/kgBB selama 6-12 mingguselama 6-12 minggu
b. Bila tergantung steroid diberikan b. Bila tergantung steroid diberikan siklofosfamid 2mg/kgBB selama 8-12 siklofosfamid 2mg/kgBB selama 8-12 minggu. Bila dengan cara ini gagal diberi minggu. Bila dengan cara ini gagal diberi siklosporin 5 mg/kgBB 6-12 bulansiklosporin 5 mg/kgBB 6-12 bulan
c. Bila resisten terhadap steroid diberikan c. Bila resisten terhadap steroid diberikan siklosporin 5 mg/kgBB selama 6-12 bulansiklosporin 5 mg/kgBB selama 6-12 bulan
Glomerulonefritis Fokal Glomerulonefritis Fokal SegmentalSegmental
1.1. Diberi steroid setara dengan prednison Diberi steroid setara dengan prednison 60 mg/hari selama 6 bulan60 mg/hari selama 6 bulan
2.2. Bila resisten atau tergantung steroid beri Bila resisten atau tergantung steroid beri siklosporin 5 mg/kgBB selama 6 bulansiklosporin 5 mg/kgBB selama 6 bulan
3.3. Bila terjadi remisi siklosporin diturunkan Bila terjadi remisi siklosporin diturunkan 25% setiap 2 bulan25% setiap 2 bulan
4.4. Bila gagal pemberian siklosporin Bila gagal pemberian siklosporin dihentikandihentikan
Nefropati membranosaNefropati membranosa1.1. Metilprednisolon 1 g/hari bolus i.v selama Metilprednisolon 1 g/hari bolus i.v selama
3 hari3 hari2.2. Kemudian diberi steroid setara prednison Kemudian diberi steroid setara prednison
0,5 mg/kgBB/hari selama 1 bulan lalu 0,5 mg/kgBB/hari selama 1 bulan lalu diganti dengan klorambusil 0,2 diganti dengan klorambusil 0,2 mg/kgBB/hari atau siklofosfamid 2 mg/kgBB/hari atau siklofosfamid 2 mg/kgBB/hari selama 1 bulanmg/kgBB/hari selama 1 bulan
3.3. Prosedure no.2 diulang kembali sampai Prosedure no.2 diulang kembali sampai seluruhnya dari prosedure no. 2 seluruhnya dari prosedure no. 2 sebanyak 3 kali sebanyak 3 kali
4.4. Dapat remisi spontan, prognosis bagus Dapat remisi spontan, prognosis bagus sp 15 thsp 15 th
Glomerulonefritis Glomerulonefritis Membrano ProliferatifMembrano Proliferatif
Pemberian steroid terbukti tidak Pemberian steroid terbukti tidak efektif dibanding pasien pediatrikefektif dibanding pasien pediatrik
Dianjurkan pemberian aspirin 325 Dianjurkan pemberian aspirin 325 mg/hari atau dipiridamol 75 mg tiga mg/hari atau dipiridamol 75 mg tiga kali sehari atau gabungan keduanya kali sehari atau gabungan keduanya selama 12 bulanselama 12 bulan
Nefropati IgANefropati IgA
1.1. Bila proteinuri kurang dari 1 gram, Bila proteinuri kurang dari 1 gram, hanya observasihanya observasi
2.2. Proteinuria < 3 gram, dengan fungsi Proteinuria < 3 gram, dengan fungsi ginjal normal, hanya observasi. Bila ginjal normal, hanya observasi. Bila dengan insufisiensi ginjal beri “fish oil”dengan insufisiensi ginjal beri “fish oil”
3.3. Bila proteinuri > 3 gram dengan CCT Bila proteinuri > 3 gram dengan CCT >70 ml/menit beri steroid setara >70 ml/menit beri steroid setara prednison 1 mg/kgBB selama 2 bulan prednison 1 mg/kgBB selama 2 bulan lalu “tappering off” secara perlahan lalu “tappering off” secara perlahan sampai 6 bulan. Tetapi bila CCT <70 sampai 6 bulan. Tetapi bila CCT <70 ml/menit, hanya diberi “fish oil”ml/menit, hanya diberi “fish oil”
Pengobatan dengan ACEI dan Pengobatan dengan ACEI dan Angiotensin Reseptor-Bloker Angiotensin Reseptor-Bloker (ARB)(ARB)
Kombinasi ACEI dan ARB Memberi efek Kombinasi ACEI dan ARB Memberi efek antiproteinuri pada GN primer yang lebih antiproteinuri pada GN primer yang lebih besar dibandinglkan bila hanya memakai besar dibandinglkan bila hanya memakai ACEI atau ARB saja.ACEI atau ARB saja.
DiitDiit
Diit protein 0,6 gram/kgBB ditambah Diit protein 0,6 gram/kgBB ditambah dengan jumlah gram protein sesuai dengan jumlah gram protein sesuai jumlah gram proteinurijumlah gram proteinuri
Sindroma Nefrotik Sindroma Nefrotik yang resisten thd yang resisten thd pengobatan pengobatan
1.1. Mycophenolate mofetil (MMF) Mycophenolate mofetil (MMF) Dosis 2 X 0,5-1 gram, memiliki Dosis 2 X 0,5-1 gram, memiliki kemampuan sebagai kemampuan sebagai imunosupresanimunosupresan
2.2. Pengobatan dengan LDL-apheresisPengobatan dengan LDL-apheresis
Pengobatan optimal Pengobatan optimal sindroma nefrotiksindroma nefrotik
1.1. ACEI atau/dengan ARBACEI atau/dengan ARB
2.2. Resriksi proteinResriksi protein
3.3. Pemberian anti-hipertensi untuk Pemberian anti-hipertensi untuk menekan tekanan darah< 125/80 mmHgmenekan tekanan darah< 125/80 mmHg
4.4. Pemberian antilipid golongan statinPemberian antilipid golongan statin
5.5. Berhenti merokokBerhenti merokok
TERIMA KASIHTERIMA KASIH