Nephrotic syndrome

SMF Ilmu Penyakit Dalam

2015
SPECTRUM DISEASES IN
NEPHROLOGY
Water,electrolyte,acid-base disorders
Urinary infections
Nephrolithiasis
Glomerulonephritis, vasculitis, tubulointerstitial
nephritis
Hypertension
Acute renal failure
Chronic renal failure
Dialysis
Kidney transplant
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 Proteinuria : adult >3.5g/day; child
coincides with intercurrent infection >40mg/hour per m2
Asymptomatic hematuria + proteinuria between attacks Hipoalbuminemia <3.5g/dL
Edema
Hipercholesterolemia
Nephritic syndrome Lipiduria
Oliguria
Hematuria: red cell casts Chronic Glomerulonephritis
Proteinuria : usually <3g/day Hypertension
Edema Renal Insufficiency
Hypertension Proteinuria
Abrupt onset, usually self-limiting 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
 Nephrotic Syndrome
Definition
A clinical entity of multiple causes
characterized by :
Proteinuria > 3.5 gram / day
Children : >2 gram/day
Edema
PURE
Hypoalbuminemia (< 3.0 g/dl)
+ Hypercholesterolemia Biasanya pada MCN
+ Lipiduria (oval fat bodies)

+ Hematuria NONPURE
+ Hypertension
+ Uremia Biasanya non MCN
Nephrotic syndrome causes
(primary :idiopathic ; secondary : evidence the causes)

Histologic class Causes

Minimal change Primary (commonly in children),
secondary : viral, parasit, allergy,
drugs (NSAIDs,interferon-
a,ampicillin,rifampicin,captopril,le
ukemia,lymphoma), SLE
Focal sclerotic glomerulosclerosis Primary, secondary (usually non-
nephrotic) : hyperfiltration (single
kidney,reflux nephropathy,very
obese,kidney transplant),viral
(CMV,HIV), SLE,
heroin,pamidronate
Membranous nephropathy 75% primary,secondary :
SLE,hepatitis B;C, drugs
(NSAIDs,penicillamine,captopril,a
nti TNF therapy)
Membranoproliferative/mesangioc Primary, secondary : hepatitis
apillary GN C,B; infective endocaarditis, SLE,
Age-Associated Prevalence of Nephrotic Syndrome (P.A)
CHILDRE ADULT
% N %
% 100 OTHER
5
4 90 LUPUS 10,8
2 AMYLOID
5 5,9
1 DIABETES
80 1,6
7
OTHER
70 PROLIFERATIVE 16

60 MCGN
9,8

50
MEMBRANOUS
19,7
40
76

30 FSGS 11,8

20
MINIMAL 22
10 CHANGES

ALL
0 10 20 30 40 50 60 70 80 ALL
CHILDREN AGE AT ONSET OF NS ADULTS
Cohen AH, Glassock RJ; 1999
Percentage of primary glomerular diseases distributed by age
group in patient presenting with nephrotic syndrome

Histopathologic diagnosis Age 15-35 years Age 36-50 years Age >50 years
N=75 (%) N=45 (%) N=37 (%)
MCD 21.3 8.9 16.2
FSGS 24.0 31.1 32.4
MN 8.0 31.1 18.9
MPGN 2.7 0.0 0.0
IgAN 29.3 17.8 10.8
Non-IgA mesangial proliferative 12.0 11.0 21.6
GN
Congenital glomerulopathies 2.7 0.0 0.0

Data dari : Malaysian pathology registry 2008

Schematic drawing of the glomerular barrier. Podo = podocytes; GBM = glomerular basement
membrane; Endo = fenestrated endothelial cells; ESL = endothelial cell surface layer (often referred to
as the glycocalyx). Primary urine is formed through the filtration of plasma fluid across the glomerular
barrier (arrows); in humans, the glomerular filtration rate (GFR) is 125 mL/min. The plasma flow rate
(Qp) is close to 700 mL/min, with the filtration fraction being 20%. The concentration of albumin in
serum is 40 g/L, while the estimated concentration of albumin in primary urine is 4 mg/L, or 0.1% of its
concentration in plasma. Reproduced from Haraldsson et al, Physiol Rev 88: 451-487, 2008, and by
 Proteinuria in Adults
Presentation by Severity of Proteinuria

< 3.0 g/day

asymptomatic
> 3.5 g/day
asymptomatic
swelling of feet / face
shortness of breath
(in aged + heart / liver disease)
+ gross hematuria + features of hypertension

Cattran DC, 1999

 Formation of Nephrotic Edema
Underfill Overfill
Proteinuria Primary tubular
defect causing
Hypoalbuminemia Sodium retention

Plasma colloid
oncotic pressure
Starling forces
Plasma volume Plasma volume
normal/
Renin-angiotensin
system activated
Aldosterone
Vasopressin
Atrial Natriuretic
Peptide (ANP) Vasopressin
ANP Aldosterone
normal/low normal
* The kidney is relatively resistant
Sodium * to ANP in this setting, so it has
Water little effect in countering retention
retention
retention
Edema Feehally J, Johnson RJ;2000
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

Minimal Change Disease
Cotran RS, Kumar V, Robbins SL; 1994
Focal Segmental
Glomerulosclerosis
Membranoproliferative GN
Mesangioproliferatip GN
Rapidly progressive (crescentic)
glomerulonephritis
 Nephrotic Syndrome
Diagnosis / Prognosis

% of
Adults Children
Cure/ESRD
Primary GN 75% 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.)

% of
Primary GN Adults Children
Cure/ESRD
(cont.)
MPGN 3-5% 1% 33/20

Crescentic 1-2% 1% 33/40

Secondary GN 25% 5% 70/30

Cattran DC, 1999

 Diagnosis
History and physical exam:preexisting
disease (DM,infections,drug, arthritis, rash),
diabetic retinopathy,malignant
hypertension, malignancy.
Laboratory
:CBC,electrolyte,RFT,albumin,lipid
profile,urinalysis,ANA test,total complement
levels,serum and urine
elektrophoresis,hepatitis
B,streptococcal,VDRL
Renal biopsy
Indications Renal Biopsy in NS
Adult : for all caused by primary renal
disease
Children 1-6 years has failed with 4 week
course of prednisone, or suspect non
minimal change GN
 DIAGNOSTIC PROCESS
>3.5 g/day
Nephrotic Syndrome

Glucose High Normal Glucose

Consider : No Family History

Family History of
Diabetic of Kidney Disease
Kidney Disease
-glomerulosclerosis

Consider :
Alports disease
Or
Fabrys disease
EXAMINE
SEROLOGY
Al-Haidary A, van Wyck DB; 1998
 EXAMINATION SEROLOGY

Elevated Low Positive Positive Serologic Hepatitis B

ANA C3, C4 ANCA anti-GMB examination or
antibody NEGATIF HIV
antigenemia

Consider Consider Consider Consider Consider Consider

Lupus GN Lupus GN Systemic Goodpatures Focal sclerosis Hepatitis
Post Infectious GN vasculitis Syndrome Minimal change or
Cryoglobulinemia or disease AIDS related
or Wegeners Drugs nephropathy
Membrano granulomatosis
proliferative GN

RENAL BIOPSY

TREAT UNDERLYING DISEASE

PREVENT SECONDARY PROGRESSION
Al-Haidary A, van Wyck DB; 1998
Consideration kidney biopsy
for nephrotic syndrome
Ne No
Kydney
TreatNo
Good
as Histology
with
Treat
Refer
steroid
forfor
Kidney
Type
2 months
Biopsy
Treatment of nephrotic syndrome
GENERAL (conservative)
Diet : protein 0.6-0.8 g/kgBW, low fat
Correction hypoalbuminemia
Treat edema
Treat infection
Treat hypertension
Treatment proteinuria
Dypiridamole,warfarin
Treatment hypercholesterolemia
SPECIFIC THERAPY
For secondary causes : treat underlying disease
Primary (idiopathic) :
- Steroid
- Cytotoxic agents :
cyclosporine,cyclofosfamide,chlorambucyl,mycophenolate
mofetil.
Response to therapy
Complete response (remission) is a reduction in proteinuria to
300 mg/day.
Partial response is a reduction in proteinuria of 50 percent, with
absolute values between 300 mg and 3.5 g/day or proteinuria
less than 3.5 g/day with a normal serum albumin concentration
Relapse is return of proteinuria to approximately 3.5 gm/day in
patients who had previously undergone a complete or partial
remission.
Frequent relapsers if they have three or more relapses per year.
Glucocorticoid-dependence refers to relapse while on therapy or
requirement for continuation of steroids to maintain remission
Glucocorticoid-resistance refers to little or no reduction in
proteinuria after 16 weeks (in children : 4 weeks) of adequate
prednisonetherapy, or some reduction in proteinuria but do not
meet the criteria for partial remission.

Clin J Am Soc Nephrol.

2007;2(3):445-53.
 Management of Edema in Nephrotic Syndrome
Oral loop diuretic e.g. Furosemide 40 mg bid
Bumetanide 1 mg bid
No response Monitor serum K+
Response If hypokalemic :
Double dose until diuresis Add : K
or ceiling dose reached supplements
Reduce Furosemide 250 mg bid Bumetanide 5 mg bid Or Amiloride 5-20
stepwise to mg daily
No response
maintenance Or Spironolactone
dose as Add : oral Thiazide e.g. 50-200 mg daily*
diuresis Hydrochlorothiazide 50 mg bid
continues Metolazone 2.5-5 mg daily
No response
Change loop diuretic to IV bolus bid * Spironolactone is less
effective in nephrotic
No response syndrome than in
cirrhosis and is often
Add : 20% human albumin 50-100 ml IV poorly tolerated
followed by IV bolus diuretic because of
gastrointestinal side-
No response
effects
Mechanical ultrafiltration

Feehally J, Johnson RJ,;2000

 Correction of Albuminemia
Infusion of Na+ free albumin induces diuresis

Treatment of Infections
Use appropriate antibiotics
Dipyridamole and Warfarin Plus Regimen
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 Reducing
of
Hypertension 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
Inhibit hypertrophy in glomerular and tubular cells
Reduce mesangial injury and proliferation
Reduce risk of tubulointerstitial damage

Toto RD; 1997

 ACE Inhibition and Glomerular Function
Afferent Glomerulus
Bowmans
Arteriole Capsule

BP

Filtered
GCP Proteins

Efferent
Arteriole
EAR

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

Steroid
Histologic Patterns and Steroid Responsiveness in
Diseases Causing Nephrotic Syndrome
Steroid Minimal change
responsive disease (MCD)

Mesangial
hypercellularity

Focal segmental
IgM Dense
glomerulosclerosis
Deposit
(FSGS)
disease
Mason PD; 2000
Percentage of steroid responsiveness in distinct primary
nephrotic syndrome (adult)

Histopathologic Complete Steroid Steroid

diagnosis remission dependenc resistance
(%) e (%) (%)
MCD 36.4 59.1 4.6
FSGS 37.9 27.6 34.5
MN 17.6 17.6 64.7
IgAN 18.8 50.0 31.3
Non-IgA mesangial 37.5 50.0 12.5
proliferative GN

THE MALAYSIAN REGISTRY OF RENAL BIOPSY 2008

Treatment of primary
Minimal change
Treatment of minimal change
disease in adults
oral prednisoneat a daily dose of 1
mg/kg of body weight (maximum
dose 80 mg/day), minimum 8 weeks,
until complete remission or 16
weeks.
After attaining remission,
prednisolonewas tapered by 10
mg/week until reaching 5 mg/day;
this dose was continued for a mean
of 1 - 2 years
Cumulative rate of remission in response to
steroids in MCD (the reasons why steroid
resistance in adult is 16 weeks, and children
is 8 weeks)

Am J Kidney Dis 2002;

TREATMENT OF RELAPSE
Administer oral prednisone at a daily
dose of 1 mg/kg (maximum dose of
60 to 80 mg per day) for a minimum
of four weeks
If remission is attained, the dose is
then tapered in 5 mg increments
every week to discontinuation within
one to two months.
Steroid dependence, frequent relaps,
steroid resistance
Cyclosporine 3 mg/kg/d and
prednisone 10 mg/d until remission
or 6 months
Then maintaned : cyclosporine 2
mg/kg/d and prednisone 5 mg/d for
1-2 years, then gradually withdrawn.
Treatment of primary focal
segmental glomerulosclerosis
Treatment of primary focal
segmental glomerulosclerosis
Prednisone induces complete or
partial remission in 40 to 80 percent
of patients with relatively preserved
renal function
Initial treatment with steroid is
similar like treatment for MCD
Steroid-dependent and steroid-
resistant FSGS
Initiate cyclosporineat a dose of approximately 3 to
4 mg/kg per day (given in two divided doses)
Continue cyclosporinefor at least six months
following attainment of a complete remission and
one year following attainment of a partial remission
Maintain the remission with cyclosporine at dose 3
mg/kg per day)
Prednisoneis given concurrently at a dose of 0.15
mg/kg (maximum 15 mg/day). After six months, we
taper prednisoneto 5 or 7.5 mg/day and maintain it
along with the cyclosporinefor an additional 6 to 12
months after attaining a remission
Treatment of idiopathic
membranous nephropathy
Treatment of idiopathic
membranous nephropathy
30% spontaneous remission
Low risk : normal creatinin,proteinuria <4
gr treat conservative
High risk : normal/high creatinin,
proteinuria > 4 gr
Treatment of idiopathic
membranous nephropathy
Oral cyclophosphamide(1.5 to 2.0 mg/kg per
day) for six months plus glucocorticoids
(methylprednisolone, 1 g intravenously daily for
three days in months 1, 3, and 5, and oral
prednisone, 0.5 mg/kg every other day for a
total of six months with subsequent tapering)
Cyclosporine 3.5 mg/kg per day, with dose
adjustment to maintain a 12-hour trough
cyclosporineconcentration of 110 to 170 g/L
for 12 months . Monitor serum creatinine
concentration due to renal toxicity
Treatment of idiopathic
membranoproliferative
glomerulonephritis
No systematic evaluation of corticosteroid
therapy in idiopathic MPGN in adults
Most studies are in children
Prednisone 40 mg/m2, was given every other
day as a single morning dose for 41 months
1-2 mg/kg of prednisoneper day for 12-16
weeks, tapered over periode months to 20
mg every other day continued for 2-3 years
Dipyridamole 225 mg per day, and aspirin
975 mg per day for one year
Terima Kasih