NEPHROTIC SYNDROME

DJOKO WIBISONO 14 Maret - 2011

Glomerulus
Glomerulus: capillary network produce ultrafiltrate Glomerular filtration rate: - GBF Arterial tone - ultrafiltration pressure - Surface area mesangail cell contractility Glomerular endothelium: antithrombotic & antiadhesive

NO, ET, Prosta cyclin

Glomerular filtration barrier: Physicochemical & electrostatic charge

Anatomy of the Glomerulus

Glomerular capsule Parietal epithelial cell

Visceral epithelial cell

Capillary lumen Endothelial cell

Mesangial matrix

Mesangial cell

GBM

Primary Glomerular Diseases

Nephrotic presentation (nephrotic syndrome)

Minimal change disease (MCD) Focal segmental glomerulosclerosis (FSGS) Membranous GN Membranoproliferative GN Acute proliferative GN Crescentic glomerulonephritis (RPGN) Anti-GBM Disease IgA Nephropathy

Acute nephritis (nephritic syndrome)

Primary hematuria

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 Asymptomatic/persistent hematuria and/or proteinuria Acute glomerulonephritis RPGN, acute renal failure Nephrotic syndrome Chronic glomerulonephritis

1.

2. 3.

4.
5.

PATHOGENESIS OF GLOMERULAR INJURY

Clinicopathologic Correlates in Glomerular Disease

Clinicopathologic: induced by a variety of difference

pathogenic mechanism prompt diagnosis, optimal management and accurate prognostic requires:
1. Recognition of the presenting syndrome

2. Delineated of the underlying morphologic pattern

3. Elucidation of the specific renal limited or systemic disease.

Nomenclature

Glomerulonephritis glomerulopathy glomerular injury Glomerulonephritis: injury with evidence of inflammation such
as leukocyte infiltration, antibody deposition, and/or complement activation.

Primary or secondary acute (days or weeks), subacute or rapidly progressive (weeks or a few months), and chronic (many months or
years)

Focal (<50%) or diffuse (>50%) of glomeruli. Segmental (involve part) or global (almost all) of the
glomerular tuft.

Nomenclature (cont)

Proliferative : glomerular cell number due to infiltration

or proliferation. Intracapillary or endocapillary: endothelial or mesangial cells and extracapillary: cells in Bowman's space RPGN crescentic glomerulonephritis Membranous: dominated by expansion of the GBM by immune deposits

Sclerosis: amount of homogeneous nonfibrillar

extracellular material of the same ultrastructural and chemical composition as GBM and mesangial matrix. Fibrosis: consequence of healing of crescents (deposition of collagens type I and III)

Nephrotic Syndrome
Is

not a disease but a group of signs and symptoms seen in patients with heavy proteinuria presents with oedema proteinuria usually > 3.5g / 24hrs (>0.05g / kg / 24hrs in children) serum albumin < 30g/l other features: hyperlipidaemia, and hypercoaguable state

Pathophysiology

proteinuria: due to an increase in glomerular permeability hypoalbuminuria: occurs when liver synthesis cannot keep up with urine losses
oedema mechanism is complex and still in dispute: primary salt and water retention associated with reduced renal function as well as reduced plasma oncotic pressure are primary factors (overfill and underfill) minimal change disease fits the underfill theory best

hyperlipidaemia: increased liver synthesis hypercoagulation: increased fibrinogen and loss of antithrombin III

Primary glomerular diseases commonly causing the nephrotic syndrome

minimal change disease focal and segmental glomerulosclerosis membranous glomerulonephritis proliferative glomerulonephritis (various histology and less common cause)
membranoproliferative (mesangiocapillary) focal proliferative diffuse proliferative mesangial proliferative

Other causes of the nephrotic syndrome 1

Systemic diseases
diabetes mellitus amyloidosis SLE and other connective tissue diseases HIV/Aids,HBV,HCV

nephrotoxins
nsaids mercury poisoning penicillamine gold salts

Other causes of the nephrotic syndrome 2

Allergies
bee sting pollens poison ivy

Circulatory effects
congestive cardiac failure constrictive pericarditis renal vein thrombosis (cause or result?)

Neoplastic
leukaemia solid tumours

Nephrotic syndrome

The above causes result in glomerular proteinuria

Heavy urinary loss of proteins, including albumin, results in hypoalbuminaemia

Nephrotic syndrome

Reduced blood albumin level results in decreased intravascular oncotic pressure, thus edema develops
Loss of fluid from the intravascular compartment, causes activation of RAS, which stimulates salt and water retention and thus, worsens the oedema

Nephrotic syndrome

Most proteins are lost to the urine, except the very large proteins, e.g. lipoprotein
Due to hypoproteinaemia, the liver increases rate of protein synthesis

Nephrotic syndrome

For most proteins, the increased hepatic synthesis cannot fully compensate for the severe urine loss
But for lipoproteins, since it is retained and in addition to the increased hepatic synthesis, hyperlipoproteinaemia results

Nephrotic syndrome
As for the loss of other proteins, there is loss of anti-coagulants such as antithrombin III, and thus nephrotic syndrome could be complicated by thromboembolic disorders, such as renal vein thrombosis There is also loss of immunoglobulins, and thus, immunodeficiency of IgG may result

Clinical Features- Edema

Physical exam
Accumulates in gravity dependent tissues Puffiness around eyes Genital edema is generally painful

Muehrcke's bands in nephrotic syndrome. The white band grew during a transient period of hypoalbuminemia caused by the nephrotic syndrome.

Xanthelasma in nephrotic syndrome. These prominent xanthelasma developed within a period of two months in a patient with recent onset of severe nephrotic syndrome and serum cholesterol 550 mg/dL (14.2 mmol/L)

Clinical Features- Edema

Pathogenesis
80% of oncotic pressure due to albumin Below 2 g/dL edema accumulates Intravascular volume depletion Renin-aldosterone activation

Clinical FeaturesInfection

Bacterial infections
Prone to bacterial sepsis Cellulitis IgG levels low Factor B levels low Lymphocyte function impaired

Viral Infections
Measles may induce remission in NS Relapse preceded by viral infection

Clinical FeaturesThrombosis

Serious risk of thrombosis Increased fibrinogen concentration Antithrombin III concentration reduced NS patients resistant to heparin Platelets hyperaggregable Increased blood viscosity

Investigation of Nephrotic syndrome

Serum electrolytes, protein and lipid profile Serum urea and creatinine 24hr urine protein excretion Creatinine clearance Urine microscopy Renal biopsy Investigation for systemic illness

Laboratory Features

Hct may be elevated Hyponatremia is common Plasma creatinine is elevated in 33% of patients

Laboratory- Plasma Protein

Albumin
Hypoalbuminemia due to loss via the kidney
Urinary excretion Proximal tubular cells catabolism

Immunoglobulins
IgG levels reduced IgM levels elevated IgM-IgG-Switching

LaboratoryHyperlipidemia

Increased synthesis of cholesterol, triglycerides and lipoproteins Decreased catabolism of lipoproteins

Decreased activity of lipoprotein lipase

Decreased LDL receptor activity Increased urinary loss of HDL Lp(a) levels are elevated

Laboratory- Urinalysis

Broad, waxy casts Lipid droplets Hematuria 22.7% of MCNS Low urine sodium High osomolality

Investigation of Nephrotic syndrome

Exception to renal biopsy:

Children presenting with nephrotic syndrome are most commonly due to minimal change disease Readily responds to steroid Therefore, give empirical steroid treatment Preform renal biopsy when no reponse to steroid treatment

Indications for Biopsy

Pretreatment
Recommended
Onset age < 6 months Macroscopic hematuria Microscopic hematuria and HTN Low C3 Renal failure

Discretionary
Onset between 6-12 months or > 12 years Persistent HTN of hematuria

Indications for Biopsy

Post treatment
Steroid resistance Frequent relapsers

Nephrotic syndrome biopsy histology in adults at different ages

Management of the nephrotic syndrome

Na+< 60 mmol/24 hrs water restriction diuretics (if not volume depleted) reduced protein diet (controversial) treat infections prophylaxis for thrombosis specific therapy
corticosteroids immunosuppression

Specific treatments

Minimal change disease

prednisone for 16 weeks (p) prednisone and cyclophosphamide ( p+c)

FSGS
p, p+c, p+cyclosporine(cs)

Membranous
Ponticelli Regimen p+c

Management of the nephrotic syndrome

Type of medicines:

Diuretik loop Kortikosteroid Azatioprin Klorambusil Siklofosfamid Siklosporin-A Mikofenolat mofetil

Management of the nephrotic syndrome

Therapy

for edema

Furosemid i.v. : 0,1 0,4 mg/kg BW/hr in NaCl 0,9% or Dext 5% solution

Furosemid 6O mg in 200 ml Albumin 20% (effective for plasma albumin : <2 g/dl)

Pengobatan dengan imunosupresan

Steroid (obat utama dan tetap ada dalam setiap rejimen) Bentuk rejimen dan lama pengobatan berbeda untuk setiap kelainan histologik yang mendasari SN SN merupakan manifestasi klinik dari GN primer yang dibagi dalam dua kelompok besar:
1.Inflamasi: GNMP, GNMsP, GN kresenti 2.Non inflamasi: kelainan minimal, GNFS, nefropati membranosa (epitel)

Kelainan minimal
1. 2. 3.

Prednison 60 mg/m2 (maks 80 mg) selama 4-6 minggu Setelah 4-6 minggu prednison 40 mg/m2 selang sehari selama 4-6 minggu Dalam pemberian prednison dapat terjadi:
a.

Relaps: prednison kembali 60 mg/m2 (maks 80 mg) setiap hari sampai 3 hari bebas protein dalam urine kemudian kembali selang sehari 40 mg/m2 selama 4 minggu. Bila sering relaps ditambah siklofosfamid 2 mg/kgBB atau klorambusil 0,15mg/kgBB selama 8 minggu. Bila gagal diberi siklosporin 5 mg/kgBB selama 6-12 minggu

b. Bila tergantung steroid diberikan siklofosfamid 2mg/kgBB selama 8-12 minggu. Bila dengan cara ini gagal diberi siklosporin 5 mg/kgBB 6-12 bulan c. Bila resisten terhadap steroid diberikan siklosporin 5 mg/kgBB selama 6-12 bulan

Glomerulonefritis Fokal Segmental

1.

2.

3.

4.

Diberi steroid setara dengan prednison 60 mg/hari selama 6 bulan Bila resisten atau tergantung steroid beri siklosporin 5 mg/kgBB selama 6 bulan Bila terjadi remisi siklosporin diturunkan 25% setiap 2 bulan Bila gagal pemberian siklosporin dihentikan

Nefropati membranosa
1. 2.

3.

4.

Metilprednisolon 1 g/hari bolus i.v selama 3 hari Kemudian diberi steroid setara prednison 0,5 mg/kgBB/hari selama 1 bulan lalu diganti dengan klorambusil 0,2 mg/kgBB/hari atau siklofosfamid 2 mg/kgBB/hari selama 1 bulan Prosedure no.2 diulang kembali sampai seluruhnya dari prosedure no. 2 sebanyak 3 kali Dapat remisi spontan, prognosis bagus sp 15 th

Glomerulonefritis Membrano Proliferatif

Pemberian steroid terbukti tidak efektif dibanding pasien pediatrik Dianjurkan pemberian aspirin 325 mg/hari atau dipiridamol 75 mg tiga kali sehari atau gabungan keduanya selama 12 bulan

Nefropati IgA
1.

2.

3.

Bila proteinuri kurang dari 1 gram, hanya observasi Proteinuria < 3 gram, dengan fungsi ginjal normal, hanya observasi. Bila dengan insufisiensi ginjal beri fish oil Bila proteinuri > 3 gram dengan CCT >70 ml/menit beri steroid setara prednison 1 mg/kgBB selama 2 bulan lalu tappering off secara perlahan sampai 6 bulan. Tetapi bila CCT <70 ml/menit, hanya diberi fish oil

Pengobatan dengan ACEI dan Angiotensin Reseptor-Bloker (ARB)

Kombinasi ACEI dan ARB Memberi efek antiproteinuri pada GN primer yang lebih besar dibandinglkan bila hanya memakai ACEI atau ARB saja.

Diit

Diit protein 0,6 gram/kgBB ditambah dengan jumlah gram protein sesuai jumlah gram proteinuri

Sindroma Nefrotik yang resisten thd pengobatan

1.

2.

Mycophenolate mofetil (MMF) Dosis 2 X 0,5-1 gram, memiliki kemampuan sebagai imunosupresan Pengobatan dengan LDL-apheresis

Pengobatan optimal sindroma nefrotik

1. 2.

3.

4.

5.

ACEI atau/dengan ARB Resriksi protein Pemberian anti-hipertensi untuk menekan tekanan darah< 125/80 mmHg Pemberian antilipid golongan statin Berhenti merokok

TERIMA KASIH