PROTEINURIA &

NEPHROTIC SYNDROME
 Anatomi dan Fisiologi
Glomerulus
Setiap Ginjal: 1 juta
Glomerulus jaringan
kapiler arteriol aferen dan
eferen.
Tiga sel intrinsik
glomerulus: sel endotel
kapiler, sel epitel dg
membran basal glomerulus
(normal jika intact tidak
akan bocor), sel mesangial.
Dinding kapiler glomerulus
tdd 3 lapisan: sel endotel,
MBG, dan sel epitel viseral
glomerulus.
 Membran Basal Glomerulus/
Glomeruler Basal Membrane/ GBM

Selain intact, juga mengandung struktur protein yg

karakteristik.
Certain collagens and charged heparin like
molecules.
Pori-pori GBM yang tersebar mencegah molekul
besar (size selectivity) dan ion-ion charged (charge
selectivity) melewati GBM.
 Proteinuria Normal dan Abnormal
Normal, urin mengandung sejumlah kecil protein
(berat molekul rendah dan Tamm-Horsfall), <150
mg/ hari pd orang dewasa. Olah raga berat,
demam, dan posisi berdiri lama akan
meningkatkan proteinuria.
Abnormal:
1. Glomerular proteinuria: protein BM besar, bbrp
gram sehari. Etiologi: glomerulonefritis primer atau
sekunder spt: DM, SLE, amiloidosis
2. Tubular proteinuria: protein BM kecil, <1 g/ hari.
 Defining Proteinuria

Degree of Proteinuria 24 Hour Urine Urine Dipstick

Normal <30 mg albumin None

/day
Microalbuminuria 30 300 mg/day None

Macroalbuminuria 300 3500 mg/day >15 mg/dl (trace)

Nephrotic Range >3.5 g /day >300 mg/dl (3+)

Office Urine Dipstick

Trace 15 mg/dl
1+ 30 mg/dl
2+ 100 mg/dl
3+ 300 mg/dl
4+ 2000 mg/dl
 According to the source:
Glomerular proteinuria : high molecular
weight plasma protein
Tubulus proteinuria : lower molecular weight
protein
NEPHROTIC SYNDROME
 Definition
A syndrome consist of : massive
proteinuria, hypoalbuminemia, oedema
and hypercholesterolemia
Clinical remarks :
Protein urine > 3,5 gr/24 hr
Albumin < 3,5 gr/dl
Pitting oedema
With or without dislipidemia
NEJM 1998; 338:1202
 Etiology
Nephrotic Syndrome is one of the clinical
syndromes with many causes and many histologic
abnormalities

Briefly, there is idiopathic (primary glomerular

disease) and those glomerular disease that arises
as a complication of other diseases (Table 1)
 TableSyndrome
Idiopathic Nephrotic 1. Causes due
of Nephrotic Syndrome
to primary glomerular disease
Nephrotic syndrome associated with specific etiologies events /
complication of other diseases :
1. Medications
Mercury, gold, heroin, probenecid, captopril, NSAID, lithium, IFN
2. Allergens, venoms, immunizations
Bee sting, Pollen
3. Infections
Bacterial, Viral, Protozoal, Helminthic.
4. Neoplastic
Solid tumor of lung, stomach, colon, breast. Hodkin disease. GVHD
5. Multisystem disease
SLE, Henoch-schnlein Purpura, Amyloidosis
6. Heredofamilial and metabolic disease
Diabetes mellitus, Hypothyroidism, Graves disease, Amyloidosis, Podocyte
mutation, Congenital nephrotic syndromes

7. Miscelaneous
Pregnancy associated, chronic renal allograft failure
Table 2. Causes of SN grouped by pathology
Focal Segmental Glomerular Sclerosis (FSGS, 40%)
Sustained glomerular hyperfiltration, diabetes
HIV variant, heroin
Membranous nephropathy (MN, 30%)
Infection (HBV, HCV, Syphilis)
Autoimune (SLE, RA, Sjorgen)
Carcinomas (breast, lung, colon)
Drugs (gold, penicilamine, ACE-I, NSAIDs)
Minimal Change Disease (MCD, 20%)
NSAIDs, Hodgkins, HIV
Membranoproliferative Glomerulonephritis (MPGN, 5%)
Type I (subepitelial C3 & Ig deposits)
Infection (HIV, HBV, HCV)
Immunecomplex disease (SLE, cryoglobulinemia, Sjorgens)
Lymphoproliferative (leukemia, lymphoma)
Type II (dense deposit disease, c3 only = autoantibody)
Fibrillary-immunotactoid glomerulopathy (1%)
Mesangial Proliferative GN (atypical MCD/FSGS, 5%)
IgA Nephropathy (asx hematuria)
 Patophysiology
Physiologicallynormal adults :
150 200 mg/day (maximal)
30 mg/day for albumin (maximal)
3 possible mechanism of overt proteinuria:
Excessive leak of protein into glomerular filtrate
Lack of reabsorbtion of protein normally present
in glomerular filtrate
Tubular excretion of protein
Nephrotic Syndrome : Glomerular Filtration
Depends on 3 main factors :
Structural and physical properties of the filter
Physicall properties of molecules
undergoing filtration
Flow dynamics within glomerular capillaries
 The Filter
Importance of electrical charge properties of
capillary wall
Anionic molecules were > restricted than cationic
of the same size and shape
 The podocyte-slit membrane unit
Slit membrane

Filtration barrier: Podocyte

Basement Foot process
Endothelium membrane

Glomerular basement
membrane
Podocyte-slit-membrane Zipper-
like struct.
Selectivefilter
Sensing-signaling function

Roleof the podocyte-GBM endothelium pore

contact and the podocyte

cytoskeleton

16
Blood enters the glomerular capillaries and is filtered across the endothelium and
the glomerular basement membrane and through the filtration slits between
podocyte foot processes to produce the primary urine filtrate.
 Physical properties of filtration molecules
Size
molecules lower filtration
Larger
Low molecular radius higher filtration
Molecular charge
Cationic dextrans > neutral dextrans (same size)
Shape
Deformability and flexibility
Dextran (uncoil-able) > clearance than globular
protein that tightly bound (7 x higher)
Tubular reabsorption
Normally some proteins, peptides,
immunoglobulin fragments are freely filtered
Almost completely absorbed in proximal
tubule and undergo intracellular catabolism
 Edema
Accumulation of visible or palpable
accumulation of interstitial fluid :
Fluidmove from plasma into interstitial
Kidney must retain sufficient salt and water
 OVERFILL

UNDERFILL
 Hyperlipidemia
Cholesterol, phospholipids, triglycerides tend
to be elevated
Inverse relation to serum albumin
concentration and also plasma oncotic
pressure
Lipoprotein was synthesized together as liver
try to produce albumin
 Hypoproteinemia
Hypoalbuminemia mainly caused by loss and
degradation of reabsorbed protein
Hepatic albumin synthesis cannot keep pace
with the losses (8 14 gr/day Albumin)
Oncotic pressure of plasma protein control
stimulation of albumin production
Production also limited by availability of amino
acids, hepatic disease, systemic disease, hormon
 Special clinical precautions
Drug Metabolism
Hypoalbuminemia limits sites available for protein
binding increasing circulating free drug &
increasing first-pass hepatic drug removal.

Reduced protein binding results both from

hypoalbuminemia & from a decrease in albumin's
affinity for drugs.

The clinical consequences of altered protein binding

may be difficult to predict: decreased binding
allows for a higher concentration of free drug, but
this effect may be counteracted by a larger volume
of distribution or faster metabolism of the drug (or
both).
 Clinical management
Edema
Symptomatic relief not treating underlying dis.
Dietary salt restriction and diuretics
Severe postural hypotension, prerenal
azotemia, and shock may follow in extremely
low albumin level
Severe edema may need intensive and
careful diuretic program
 Hypoalbuminemia
Intravenous albumin infusion may also
increase proteinuria
May decrease albumin synthesis and
increase extra-renal albumin degradation
Transient effect only (1 2 days)
May be helpful for short periods of severe
hypoalbuminemia with hypotension or those
needed powerful diuretic use
 Proteinuria
The best treatment is to induce remission of
underlying disease
Nephrectomy for those already have ESRD but
with proteinuria, edema and hypoalbuminemia
remain severe and disabling
Reduction of GFR ACE-I/ARB can help (NEJM
1993;329:145 & 2001;345:861; Lancet 1997
1992;349:1857 & 1999;354:359)
 Primary glomerular Disease :
Steroid + cytotoxic therapy : cyclophosphamide,
chlorambucil
NEJM 1989;320:8 & 1992;327:599
Prednison 1 mg/kg/day for 6 8 weeks (esp. in
MCD, MN, FSGS)
Cyclophosphamide 2 mg/kg/day oral ~ cystitis
hemorrhagik, hypoplasia gonad
Cyclosporin-A initial 5 mg/kg/day for 2 months,
then tappering down to 2,5 mg/kg/day (esp. in
membranous) ~ Nephrotoxic
Azathriopin 2 mg/kg/day
MMF 2 gr/day for 6 months then tappering down
to 0,5 1 gr/day
Secondary glomerular disease :
Treat underlying disease
 General measures
Infection
observation
Drug dosing
Supplementation of vitamin and iron as
needed
Thrombosis and bleeding may occur as
hemostatic role proteins are loss
 Renal Biopsy
Inchildren since very likely minimal lesion
may proceed steroid therapy without biopsy
confirmation
Those who fail by first therapy or in older
patient other histologic for of nephrotic
syndrome is likely :
Responsiveness to steroid / immun-suppresant
Different course of disease
Different prognosis

biopsy confirmed histologic diagnosis are

very useful in the management
THANK YOU