Sindroma Nefrotik

Kuliah Semester VII FKUA

Ilmu Penyakit Dalam - Nefrologi

Divisi Nefrologi & Hipertensi Lab-SMF Penyakit Dalam

FK Unair RSU Dr. Soetomo, Surabaya

Clinical Presentations of Glomerular Disease

Asymptomatic
Proteinuria 150 mg to 3 g per day
Hematuria > 2 red blood cells per high-power field (>10x10 6 cells/L)
in spun urine (red blood cells usually dysmorphic)

Macroscopic hematuria

Nephrotic Syndrome

Brown / red painless hematuria (no clots); typically

coincides with intercurrent infection
Asymptomatic hematuria + proteinuria between attacks

Proteinuria : adult >3.5g/day; child

>40mg/hour per m2
Hipoalbuminemia <3.5g/dL
Edema
Hipercholesterolemia
Lipiduria

Nephritic syndrome
Oliguria
Hematuria: red cell casts
Proteinuria : usually <3g/day
Edema
Hypertension
Abrupt onset, usually self-limiting

Chronic Glomerulonephritis
Hypertension
Renal Insufficiency
Proteinuria > 3g/day
Shrunken smooth kidneys

Rapidly progressive glomerulonephritis

Renal failure over days / weeks
Proteinuria : usually <3g/day
Hematuria : red cell casts
Blood pressure often normal
May have other features of vasculitis

Feehally J, Johnson RJ,;2000

OCallaghan C, Brenner BM; 2000

Droste C, von Planta M; 1992

Schematic Representation of a Normal Glomerular Lobe

Epithelial Cell

Foot Process

Basement membrane
Endothelial Cell
Mesangial Cell
Mesangial Matrix

Cotran RS, Kumar V, Robbins SL; 1994

Nephrotic Syndrome
Definition
A clinical entity of multiple causes
characterized by :
Proteinuria > 3.5 gram / day
Edema
Hypoalbuminemia (< 3.0 g/dl)
+ Hypercholesterolemia
+ Lipiduria (oval fat bodies)

Nephrotic Syndrome
Causes
Primary causes

Minimal change
disease
Membranous
nephropathy

Secondary causes

Diabetes Mellitus
Systemic / vascular diseases (immune
complex diseases) : SLE , Periarteritis Nodosa ,
Amyloidosis

Focal segmental
glomerulosclerosis

Drugs : NSAIDs, -interferon, pencillamine, gold

Proliferative

Allergy : pollen, house dust, insect/ snake bites,

IgA Nephropathy
SLE
Post infective
(HBV, HCV, HIV,
typhoid, malaria
etc)

(membranous nephropathy), phenytoin / dilantin,

lithium (chronic interstitial nephritis)
immunization, tetanus, smallpox

Malignancy : Hodgkins disease, mycosis

fungoides, CML (membranous GN)

Renal Vein Thrombosis

Pregnancy

Minimal Change Disease

Cotran RS, Kumar V, Robbins SL; 1994

Robbins and Cotran Pathologic Basis of Disea

SKEMA
2010

GLOMERULUS

GLOMERULUS

www.marvistavet.com

GLOMERULUS
Electron micrograph

Oxford Textbook of Clinical Nephrology, 3rd

Normal Podocyte Structure

Normal Podocyte Structure. Scanning electron microscope (SEM) micrograph of a

glomerular podocyte as seen from the urinary space. The large cell body sends out
thick primary processes that futher ramify into fine secondary (foot) processes that
interdigitate with foot processes from adjacent podocytes. Under the foot processes
is the glomerular basement membrane that surrounds the glomerular capillary (not
visible in this view).

INTACT PODOCYTES

EFFACED PODOCYTES

Differentiation Between Nephrotic

and Nephritic Syndrome
Typical
features

Nephrotic

Nephritic

Onset

Insidious

Abrupt

Edema

++++

++

Blood pressure

Normal

Raised

Jugular venous
pressure

Normal / low

Raised

Proteinuria

++++

++

Hematuria

May/ may not

occur

+++

Red-cell casts

Absent

Present

Serum albumin

Low

Normal/ slightly
reduced
Feehally J, Johnson RJ,;2000

Common Glomerular Disease Presenting as Nephrotic Syndrome in Adults

Disease
Minimal change disease

Association

Serologic tests

Allergy, atopy, NSAIDs, Hodgkins disease

None

African-American

HIV infection

HIV antibody

Heroin

Drugs, gold, penicillamine, NSAIDs

Infection : hepatitis B, C, malaria

HBsAg, anti-HCV antibody

Lupus Nephritis

Anti-DNA antibody

Malignancy breast, lung, gastrointestinal tract

Membranoproliferative
glomerulonephritis (Type I)

C4 nephritic factor

C 3, C 4

Membranoproliferative
glomerulonephritis (Type II)

C3 nephritic factor

C 3, C 4 normal

Cryoglobulinemic MPGN

Hepatitis C

anti-HCV antibody, rheumatoid

factor, C3, C4 , CH50

Myeloma

Serum protein electrophoresis,

urine immunoelectrophoresis

Rheumatoid arthritis, bronchiectasis, Crohns

disease (and other chronic inflammatory
conditions), familial Mediteranian fever

Other diabetic microangiopathy

None

Focal segmental
glomerulosclerosis

Membranous Nephropathy

Amyloid

Diabetic nephropathy

Feehally J, Johnson RJ,;2000

Age-Associated Prevalence of Nephrotic Syndrome (P.A)

%
5
4
2
5
1
7

% 100

ADULT

CHILDRE
N

OTHER

LUPUS

90

10,8

AMYLOID

5,9
1,6

DIABETES

80

OTHER
PROLIFERATIVE

70

16

MCGN

60
50
76

9,8

MEMBRANOUS

19,7

40
30

FSGS

11,8

20
MINIMAL
CHANGES

10
ALL
CHILDREN

10

20

30

40

22

50

60

AGE AT ONSET OF NS

70

80

ALL
ADULTS
Cohen AH, Glassock RJ; 1999

Nephrotic Syndrome
Diagnosis / Prognosis
Adults

Primary GN 75%

Children

% of
Cure/ESRD

95%

MCD

15%

80%

100/0

FSGS

20%

15%

40-60/50

MGN

30%

50/25

IgAN

10%

33/50
Cattran DC, 1999

Nephrotic Syndrome
Diagnosis / Prognosis
(cont.)

Primary GN
(cont.)

Adults

Children

% of
Cure/ESRD

MPGN

3-5%

1%

33/20

Crescentic

1-2%

1%

33/40

Secondary GN

25%

5%

70/30

Cattran DC, 1999

PROTEINURIA

PROTEINURIA
Marker of Increased Cardiovascular Risk
Risk factor for progressive renal disease :
Diabetic Nephropathy
Hypertensive Nephrosclerosis
IgA Nephropathy
Other Glomerulonephritis

Toto RD; 1997

NORMO , MICRO & MACROALBUMINURIA

Micral test

RIA

Albustix-positive

Micro
Macro
Nephrotic
Albuminuria Albuminuria Syndrome

Normal
Range

10

30

300

mg/day

20

200

mc.g/min
Total Urinary Protein
~ 500 mg/day
Willuiams G, Pickup JC;1999

NormoMicroMacro-*)
Albuminuri Albuminuri Albuminuri
a
a
a
Albumin
Excretion
Rate
mg/day

< 30

30-300

> 300

g/minute

< 20

20-200

> 200

11%

22%

50%

Neg

Neg

Pos

Neg

Pos

Pos

Albumin
Total Urine
Protein
Albustix
Reaction
Micral Test

*) Clinical Albuminuria

Willuiams G, Pickup JC;1999

Proteinuria in Adults
Presentation by Severity of Proteinuria
< 3.0 g/day
asymptomatic
> 3.5 g/day
symptomatic
swelling of feet / face
shortness of breath
(in aged + heart / liver disease)
+ gross hematuria + features of hypertension
Cattran DC, 1999

HOW PROTEINURIA MAY CAUSE RENAL INJURY

Proximal
Proximal Cell
Cell

Protein
Protein
Molecules
Molecules

Matrix
Matrix Proteins

Cell Injury

Chemokines
Chemokines
AII
AII
MCP-I
MCP-I
ET-I
ET-I

Fibroblasts
Fibroblasts

Progressive
Progressive Renal
Renal Damage
Damage

Cytokines
Cytokines
IL-6
IL-6
PDGF-
PDGF-
TNF,
TNF, others
others

Inflammation

Macrophages
Macrophages

Collagen
Collagen

Fibrosis
Toto
Toto RD;
RD; 1997
1997

History Physical
Examination

Patients with PROTEINURIA

Urine dipstick test

24-hr urine protein > 150 mg/day

24-hr urine protein < 150 mg/day

PATHOLOGIC

Probably normal

Urine protein electrophoresis 24-hr collection

< 3.5 g/day

> 3.5 g/day : Nephrotic Syndrome

Glucose
Intolerance

No Glucose
Intolerance

Consider :
Diabetic
-glomerulosclerosi
s
Family History of Kidney Disease
Consider :
Alports disease or Fabrys disease
Elevated ANA
Consider
Lupus GN

Abnormal proteins

Exclude :
Exclude :
CHF
Causes of Nephrotic
Hypertension
Syndrome
Nephritis
Consider :
Fever
Transient proteinuria
ATN
Benign persistent proteinuria
Orthostatic proteinuria

Exclude :
Multiple
Myeloma

Consider :
Amyloidosis
or
Light-chain Disease

No Family of History Kidney Disease

EXAMINE SEROLOGY

Low C3, C4
Positive ANCA Positive anti-GMB antobody
Consider
Consider
Consider
Systemic vasculitis
Lupus GN
Goodpatures Syndrome
or
Post Infectious GN
Wegeners granulomatosis
Cryoglobulinemia
or
RENAL BIOPSY
Membrano proliferative GN

Serologic examination
Hepatitis B
negative
or
HIV antigenemia
Consider
Consider
Focal sclerosis
Hepatitis
Minimal change disease
or
Drugs
AIDS related nephropathy

TREAT UNDERLYING DISEASE

PREVENT SECONDARY PROGRESSION

Al-Haidary A, van Wyck DB; 1998

Evaluation of Isolated Asymptomatic Proteinuria

Asymptomatic proteinuria

Quantitative protein excretion

Measure glomerular filtration rate (GFR)
Normal GFR
Non-nephrotic proteinuria
Recumbent overnight

Persistent fixed
proteinuria
Reassess at 6-12 months
Urine protein
GFR
Blood pressure

If normal GFR and BP

persists : reassess
annually

Reduced
Dipstic negative
Orthostatic
proteinuria
No further action
If GFR or BP abnormal, if
proteinuria increases

GFR
Serologic
test
Ultrasound
Renal
Biopsy

Feehally J, Johnson RJ,;2000

Patients with
PROTEINURIA
History Physical
Examination

Urine dipstick test

24-hr urine protein

> 150 mg/day

< 150 mg/day

Probably normal

PATHOLOGIC

Urine protein electrophoresis

24-hr collection
Al-Haidary A, van Wyck DB; 1998

Urine protein electrophoresis

24-hr collection

> 3.5 g/day

Nephrotic
Syndrome

< 3.5 g/day

Exclude :
CHF
Hypertension
Nephritis
Fever
ATN

Abnormal proteins
Exclude :
Multiple
Myeloma
Exclude :
Causes of
2nd Nephrotic
Syndrome

Consider
Transient proteinuria
Benign persistent
proteinuria
Orthostatic proteinuria

Consider
Amyloidosis
Or
Light-chain Disease

Al-Haidary A, van Wyck DB; 1998

>3.5 g/day
Nephrotic Syndrome

Glucose Intolerance

Consider :
Diabetic
-glomerulosclerosis

No Glucose
Intolerance

Family History of
Kidney Disease
Consider :
Alports disease
Or
Fabrys disease

No Family History
of Kidney Disease

EXAMINE
SEROLOGY
Al-Haidary A, van Wyck DB; 1998

EXAMINATION SEROLOGY

Elevated
ANA

Consider
Lupus GN

Low
C3, C4

Positive
ANCA

Positive
anti-GMB
antibody

Consider
Consider
Consider
Lupus GN
Systemic
Goodpatures
Post Infectious GN
vasculitis
Syndrome
Cryoglobulinemia
or
or
Wegeners
Membrano
granulomatosis
proliferative GN

Serologic
examination
NEGATIF

Hepatitis B
or
HIV
antigenemia

Consider
Focal sclerosis
Minimal change
disease
Drugs

Consider
Hepatitis
or
AIDS related
nephropathy

RENAL BIOPSY
TREAT UNDERLYING DISEASE
PREVENT SECONDARY PROGRESSION
Al-Haidary A, van Wyck DB; 1998

NEPHROTIC SYNDROME

Formation of Nephrotic Edema

Underfill

Overfill

Proteinuria

Primary tubular
defect causing
Sodium retention

Hypoalbuminemia
Plasma colloid
oncotic pressure
Starling forces

Plasma volume

Plasma volume
Renin-angiotensin
system activated
Aldosterone

Vasopressin

Atrial Natriuretic
Peptide (ANP)
normal/low
Water
retention

normal/

Vasopressin
normal
Sodium
retention

Edema

Aldosterone
ANP
* The kidney is relatively resistant
* to ANP in this setting, so it has
little effect in countering retention

Feehally J, Johnson RJ;2000

Coagulation Abnormalities in Nephrotic Syndrome

Hepatic
synthesis

Coagulation proteins :
Fibrinogen, factors V, VII, von
Willebrand factor, protein C,
1-macroglobulin
Unchanged / reduced :
Prothrombin, factors IX, X, XI,
XII, antithrombin III

Hyperlipidemia

Accelerated
atherogenesis

Urine
Clearance

Platelet aggregability
Volume contraction
Hemoconcentration
Immobility

Arterial thrombosis

Venous thromboembolism
Feehally J, Johnson RJ; 2000

Lipid Abnormalities in Nephrotic Syndrome

Circulating Lipids
Hepatic
synthesis

Hepatic secretion
HDL
Lecithin cholesterol
acyltransferase (LCAT)
activity

VLDL very-low-density lipoproteins

HDL high-density lipoproteins
IDL intermediate-density lipoproteins

VLDL

VLDL deposition in
vascular tissues

IDL

Catabolism , Endothelial
lipoprotein lipase

LDL

Oxidized LDL

HDL

Atherogenecity

HDL3

Urine clearance of
smaller HDL3

HDL2

Cholesterol removal from

tissue to liver impaired

Lipoprotein
(a)

Atherogenecity

Feehally J, Johnson RJ; 2000

Indications for Renal Biopsy in Adults

a) Diagnosis what is it ?
b) Prognosis what is going to happen ?
c) Therapy what is the treatment ?

Cattran DC, 1999

Nephrotic Syndrome
Treatment

General
Diet : Protein 0.6-0.8 g/KgBB , low salt
Correction of hypoalbuminemia
Diuretics treatment
Treatment of Infection
Treatment of Hypertension
Treatment of Proteinuria
Dipyridamole + Warfarin
Treatment of Hypercholesterolemia
Specific
Steroid
Cytoxic Agents

Diuretic Treatment
Frusemide
can be used alone
increase the dose till diuresis occurs
K+ supplement often required
Spironoloactone
Should be avoided if serum K+ is high / patients with
renal impairement
Chlorthiazide
synergistic action with frusemide and spironolactone
Combination of 3 agents above
Thye WK; 1999

Management of Edema in Nephrotic Syndrome

Oral loop diuretic e.g. Furosemide 40 mg bid
Bumetanide 1 mg bid
Response

Reduce
stepwise to
maintenance
dose as
diuresis
continues

No response

Double dose until diuresis

or ceiling dose reached
Furosemide 250 mg bid Bumetanide 5 mg bid
No response

Add : oral Thiazide e.g.

Hydrochlorothiazide 50 mg bid
Metolazone 2.5-5 mg daily

Monitor serum K+
If hypokalemic :
Add : K
supplements
Or Amiloride 5-20
mg daily
Or Spironolactone
50-200 mg daily*

No response

Change loop diuretic to IV bolus bid

No response

Add : 20% human albumin 50-100 ml IV

followed by IV bolus diuretic
No response

* Spironolactone is less
effective in nephrotic
syndrome than in
cirrhosis and is often
poorly tolerated
because of
gastrointestinal sideeffects

Mechanical ultrafiltration
Feehally J, Johnson RJ,;2000

Correction of Albuminemia
Infusion of Na+ free albumin
benefit ?

induces diuresis

Treatment of Infections
Use appropriate antibiotics

Dipyridamole and Warfarin Plus Regimen

P and W + regimen (Woo Keng Thye)
Dipyridamole
anti-platelet & anti-PDGF
75 100 mg 3x/day
Warfarin
anti-thrombotic
1 3 mg

Treatment of Hypercholesterolemia
Cholesterol is toxic to mesangial cells
Use Statin
Serum albumin should be > 3.0 g/dl
Thye WK; 1999

Treatment
of
Hypertension

Reducing
Proteinuria

Angiotensin Converting Enzyme Inhibitor

(ACE I)
Angiotensin II Receptor Antagonist

(ARB)
Calcium Channel Blocker NonDihydropyridine

(CCB-nonDHPP)

ACE Inhibitors :
Renal Protective Effects
Lower blood pressure
Lower glomerular capillary pressure
Improve glomerular permeability to plasma proteins
(protein)
Inhibit hypertrophy in glomerular and tubular cells

Toto RD; 1997

REDUCING PROTEINURIA WITH ACE INHIBITORS

MAY SLOW PROGRESSION OF RENAL DISEASE

Reduce mesangial injury and proliferation

Reduce risk of tubulointerstitial damage
Improve hyperlipidemia reduce glomerular
and tubular injury

ACE Inhibition and Glomerular Function

Glomerulus

Afferent
Arteriole

Bowmans
Capsule

BP

GCP

EAR

Efferent
Arteriole

Lewis E. Contrib Nephrol 1996;118:206-213.

Filtered
Proteins

Steroid

Histologic Patterns and Steroid Responsiveness in

Diseases Causing Nephrotic Syndrome
Steroid
responsive

Minimal change
disease (MCD)

Mesangial
hypercellularity
Focal segmental
glomerulosclerosis
(FSGS)

IgM Dense
Deposit
disease
Mason PD; 2000

Cytotoxic Agents :
Cyclophosphamide
Chlorambucil
Cyclosporine
Mycophenolate mofetyl
others

Summary
A clinical entity of multiple causes
characterized by :
Proteinuria > 3.5 gram / day
Edema
Hypoalbuminemia (< 3.0 g/dl)
+ Hypercholesterolemia
+ Lipiduria (oval fat bodies)
Causes :
Primary
MCD, Membranous, FSGS, Proliferative
Secondary
DM, Systemic (SLE etc), Allergy, Drugs, Malignancy, RVT,
pregnancy

Summary (cont.)
Treatment of Nephrotic Syndrome
General
Dietary Protein 0.6-0.8 g/KgBB , low salt
Judicious use of i.v albumin
Furosemide + Spironolactone + Thiazide
Appropriate antibiotics if infection is present
Treat hypertension and reduce proteinuria with :
ACE-I , ARB , CCB-nonDHPP
Dipyridamole + Warfarin
Treat Hypercholesterolemia with Statins if serum
albumin > 3.0 g/dl
Specific
Steroid
Cytoxic Agents : Cyclophosphamide
Cyclosporine A
Mycophenolate mofetyl etc

TERIMA KASIH
Kuliah Semester VII FKUA 2003/2004
Ilmu Penyakit Dalam Nefrologi

Divisi Nefrologi & Hipertensi Lab-SMF Penyakit Dalam

FK Unair - RSU Dr. Soetomo

Glomerulonephritis
Lagrue G, Hirbec g, Bernard D, Sobel A; 1976