Transcript Idiopathic Nephrotic Syndrome

Idiopathic Nephrotic Syndrome
Dr.Fahad Gadi, MD
Pediatrics Demonstrator
King Abdulaziz University
Rabigh Medical School
Nephrotic Syndrome
Generally has a glomerular cause
Types: primary and secondary
Secondary NS : anaphylactoid
purpura, systemic lupus
erythematosus, diabetes mellitus,
sickle cell disease, syphilis,
NS: Types
Minimal change nephrotic syndrome
(MCNS)
Focal segmental glomerulosclerosis
(FSGS)
Congenital nephrosis
Membranoproliferative glomerulonephritis
(MPGN)
Membranous glomerulonephritis (MGN).
FSGS
 Second most common histologic subtype
 FSGS is always a histopathologic diagnosis
 FSGS may manifest in a fashion that is indistinguishable
from MCNS, but it may also be found only after years of
clinical nephrotic syndrome when earlier biopsies have
been interpreted as MCNS.
 FSGS is a known consequence of hyperfiltration and is
regularly seen in patients with reflux nephropathy and in
some patients with a single kidney whose other has
been lost because of conditions such as multicystic
dysplastic kidney disease
Congenital NS
Congenital nephrotic syndrome becomes
a consideration when nephrosis appears
during the first year of life and particularly
in those instances in which the clinical
syndrome starts in the first few months
MPGN
In older children and adolescents.
Clinical picture is more closely associated with a
nephritic picture, but on occasion it may appear
similar to MCNS or FSGS.
Membranous glomerulonephritis (MGN)
accounts for less than 1% of the cases of NS in
childhood and adolescence
Often associated with hepatitis or other viral
disease.
Mortality
MCNS: reported cumulative mortality rate
(at 20 y postonset) of less than 15%
(range in various studies, 5-15%).
FSGS: cumulative mortality rate is greater
than 50%
Morbidity
Hospitalization, in some instances
A prolonged period of treatment
Frequent monitoring both by parents and by
physician
Administration of medications associated with
significant adverse events
A high rate of recurrence (ie, relapses in >60%
of patients)
The potential for progression to chronic renal
failure (CRF)
Definitions
Nephrotic Syndrome (NS)- Edema,
Albumin < 2.5 mg/dL, proteinuria > 40
mg/m2*hr
Remission- Urinary protein < 4 mg/ m2*hr
or Albustix = 0/Trace for 3 consecutive
days
Steroid Responsive- Remission with
steroids alone
Definitions
Relapse- Urinary protein > 40 mg/m2*hr
or Albustix > 2+ for 3 consecutive days
Frequent Relapses- Two or more relapses
within 6 months of initial response or 4 or
more relapses within any 12 month period
Definitions
Steroid Dependence- Two consecutive
relapses occurring during corticosteroid
treatment or within 14 days of its
cessation
Steroid Resistance- Failure to achieve
response in spite of 4 weeks of
prednisone 60 mg/m2*day
Pathogenesis: not clear
Believed to have an immune pathogenesis
Despite the regular finding of elevated
levels of IgE and an association with
atopy in steroid-responsive NS, current
data merely suggest a common immune
activation rather than a direct association
Glomerular capillary permeability to
albumin is selectively increased
Epidemiology
Incidence
Incidence 2-7 new cases per 10,000
Prevalence 15.7 cases per 10,000
Age
MCD 2.5 years median age
FSGS 6 years median age
Sex
3:2 Boys; Girls in children <6 yo
Equal ratio in those older
Epidemiology
Familial incidence
European survey 63 of 1877 nephrotic
children had affected siblings
Familial NS similar with respect to
histopathology and steroid response
Epidemiology
Bonilla-Felix has noted a lower incidence
of MCD and higher incidence of FSGS than
previously reported
Gulati in 1999 reported a doubling of the
incidence of FSGS over historical controls
Associated Disorders
Atopy has been found in 34-60% of children
with MCD
Meadow reported plasma IgE levels elevated in 10 of
84 with MCD
Malignancy
Hodgkin’s disease
T cell lymphomas
Thymoma/ myasthenia gravis
Diabetes Mellitus
Clinical Features- Edema
Physical exam
Accumulates in gravity dependent tissues
Puffiness around eyes
Genital edema is generally painful
Clinical Features- Edema
 Pathogenesis
80% of oncotic pressure due to albumin
Below 2 g/dL edema accumulates
Intravascular volume depletion
Renin-aldosterone activation
Plasma volume (PV) has not always been found to be decreased
and, in fact, in most adults, measurements of PV have shown it
to be increased. Only in young children with MCNS have most
(but not all) studies demonstrated a reduced PV. Additionally,
most studies have failed to document elevated levels of renin,
angiotensin, or aldosterone, even during times of avid sodium
retention. Active sodium reabsorption also continues despite
actions that should suppress renin effects
Hematuria
Frequency of macrohematuria depends on the
histologic subtype of NS.
More common in those patients with MPGN
In MCNS has been reported to be as high as 34% of cases.
Higher percentage of patients with FSGS have
microhematuria than those with MCNS, but this
is not helpful in differentiating between types of
NS in the individual patient.
Hematuria: microscopic
Microscopic hematuria is present at the onset
of the disease in 20-30% of patients with
MCNS, but it disappears thereafter. By
contrast, microscopic hematuria is
consistently present in 80-100% of patients
with MPGN and in 60% of patients with MN.
Patients with FSGS have hematuria more
often than patients with MCNS, but the
presence of hematuria cannot be used to
distinguish between the 2 conditions.
Clinical Features- Edema
Evidence against
Analbuminemia
Steroid induced diuresis
Increased intravascular volume
Low renin/aldosterone levels
Clinical Features- Hypovolemia
Classic teaching
Not all patients are hypovolemic
Clinical Features- Infection
Bacterial infections
Prone to bacterial sepsis
Cellulitis
IgG levels low
Lymphocyte function impaired
Viral Infections
Measles may induce remission in NS
Relapse preceded by viral infection
Clinical Features- Thrombosis
Serious risk of thrombosis
Increased fibrinogen concentration
Antithrombin III concentration reduced
NS patients resistant to heparin
Platelets hyperaggregable
Increased blood viscosity
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
Immunoglobulins
IgG levels reduced
IgM levels elevated
IgM-IgG-Switching
Laboratory- Hyperlipidemia
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
Laboratory- Urinalysis
Broad, waxy casts
Lipid droplets
Hematuria 22.7% of MCNS
Low urine sodium
High osomolality
Laboratory- Proteinuria
> 40 mg/hour * m2
Urine protein/creatinine ratio > 2
Unusual to see tubular proteinuria
Selectivity Index
Clearance of IgG/ Clearance of Transferrin
MCD
53% < 0.10
13 % > 0.20
FSGS
15% < 0.10
57% > 0.20
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 or hematuria
Indications for Biopsy
Post treatment
Steroid resistance
Frequent relapsers
Steroid Sensitive Nephrotic
Syndrome- SSNS
Natural history
1 year mortality 2.5%
Late outcome of 152 patients followed 14-19 years
7.2% mortality
1/4 of patients have a single relapse
1/3 relapse occasionally
1/2 become steroid dependent
Most remit at puberty
2-7% will continue to relapse
Renal survival near 100%
Diuretic Therapy
 loop diuretics (furosemide) given orally in usual amounts
(~1-2 mg/kg/d) are safe and moderately effective
 If the edema is sufficiently intense that intravenous
diuretic therapy seems indicated, then salt-poor albumin
should be infused (usually at 1 gram/kg body weight
given IV over 2-4 hours)
 Diuretics other than loop diuretics (eg, thiazides,
spironolactone, metolazone) are generally not potent
enough alone
 diuresis but may give an added effect when combined
with furosemide. Metolazone (with or without
spironolactone) may be beneficial in combination with
furosemide for resistant edema.
Treatment- Diet
Low protein
Decreases albuminuria
Malnutrition
Salt restriction
During edema
Treatment- Antibiotics/
Immunizations
Prophylactic Penicillin with ascites
Gram negative coverage for peritonitis
Streptococcal immunization
Varicella
VZIG if exposed
Immunizations
No live viruses while on daily steroids
No oral polio for siblings
Treatment- Albumin
Controversial
Indication- Hypovolemia
Abdominal pain
Hypotension
Oliguria
Renal insufficiency
Complications
Mortality
1940’s- 40% 1 year mortality
Now 1-2%
Main cause of death
Infection
Thrombosis
Steroid: Initial therapy
 Higher dosages or longer courses of daily steroids do
not significantly change the response rate in MCNS
 90% of patients with MCNS respond to this therapy with
complete clearing of proteinuria, but only about 20% of
children with FSGS and <5% of those with MPGN
experience a clinical remission (defined as a diuresis
without complete clearing of proteinuria).
 The majority of children with MCNS will respond
between the 10th and 14th days of such therapy, but a
full course of at least 4 weeks of daily therapy is still
recommended.
 Children who do not respond (ie, complete clearing of
proteinuria) should be referred to a pediatric
nephrologistfor percutaneous renal biopsy and
consideration be given to an alternative plan of
treatment.
Corticosteroids Initiation
High dose steroids
2 mg/kg/day (max 80 mg)
60 mg/m2 (max 80 mg)
3 accepted protocols
80% respond within 2 weeks
Corticosteroids Initiation
Course
Long
Standard
Short
Days of Prednisone
2
mg/m BSA
Daily
Alt Day
42
42
28
28
14 + 6
16 + 8
Corticosteroids Initiation
Higher dosages or longer courses of daily
steroids do not significantly change the
response rate in MCNS
The intensity and duration of the initial
corticosteroid regime influences the rate
of relapse of NS
Cochrane metaanlysis: steroid
 In children in their first episode of SSNS, treatment with prednisone for at
least three months results in fewer children relapsing by 12 to 24 months
with an increase in benefit being demonstrated for up to seven months of
treatment compared with two months therapy. In a population with a
baseline risk for relapse of 60% with two months of prednisone, daily
prednisone for four weeks followed by alternate-day therapy for six months
would be expected to reduce the number of children experiencing a relapse
by about 33%.
 In comparison with three months of therapy, six months of therapy results
in a reduced risk for relapse without increase in adverse effects.
 The reduction in risk for relapse is associated with both an increase in
duration and an increase in dose.
 During daily therapy, prednisone is as effective when administered as a
single daily dose compared with divided doses.
 Alternate-day therapy is more effective than intermittent therapy (three
consecutive days of seven days) in maintaining remission.
 In relapsing SSNS, long duration of alternate-day prednisone is more
effective than the standard duration therapy for relapse originally
recommended by the ISKDC
Corticosteroids- Maintenance
Individualized for each patient
Usually tapered over 6 months- 1 year
Steroid
4 weeks: intensive (daily) treatment
8 weeks: 1.5 mg/kg/d (one dose every
other morning)
8 weeks: 1.0 mg/kg/d (one dose every
other morning)
8 weeks: 0.5 mg/kg/d (one dose every
other morning)
Relapse
No predictors of relapse
Relapses as responsive
25% spontaneously remit
Treatment deferred 5 days
Intensification of relapse treatment has
little effect on subsequent relapse rate
Corticosteroids- Relapse
60 mg/m2/day until remission
Change to alternate day
Taper over 1-3 months
Steroid Toxicity
Cushingoid habitus
Obesity
Striae
Hirsutism
Acne
Growth failure
Avascular necrosis
Osteoporosis
Steroid Toxicity
Peptic ulceration
Pancreatitis
Posterior lens opacities
Myopathy
Increased ICP
Susceptibility to infection
Indications for Alternative
Therapy-SSNS
Relapse on Prednisone Dosage >0.5
mg/kg/alt day plus:
Severe steroid side effects
High risk of toxicity- diabetes
Unusually severe relapses
Relapses on Prednisone Dosage >1.0
mg/kg/alt day
Options for Alternative TherapySSNS
Alkylating Agents
Nitrogen mustard
Cyclophosphamide
Chlorambucil
Levamisole
Cyclosporine
Cyclophosphamide- SSNS
8 weeks of 3 mg/kg/day
69% of children with SRNS remain in
remission for 1 year
44% for 5 years
Younger children do worse
Steroid dependent children do worse
2 mg/kg/day may or may not have any
benefit
Chlorambucil- SSNS
0.2 mg/kg/day for 8 weeks
Jones 1988 5 patients with SSNS
1 course induced remission for 7.4 months
2 course induced remission for 22 months
Bailey 1989 5 patients with SSNS
All remitted with 1 course
Elzouki 1990 16 patients with SSNS
56% complete remission (39 month follow)
Relapse rate cut in half
Levamisole- SSNS
Antihelmithic with immunomodulating
properties
2.5 mg/kg/qOD for 2 months
Tenbrock 1998
5 patients SSNS
5/5 complete remission
24 month followup
Levamisole- SSNS
British association for Pediatric
Nephrology
1991 61 children
Levamisole vs placebo same dose
Steroids stopped at 56 days
14/31 in levmisole group in complete
remission at 112 days
4/30 in placebo group in complete remission
Cyclosporine- SSNS
5 mg/kg/day
Used with steroids
Patients usually respond well
Cyclosporine dependence is common
Long term side effects unknown
Steroid Resistant Nephrotic
Syndrome (SRNS)
Natural history
40% ESRD by 5 years ISKDC
Tejani 70% ESRD by 2 years
12% of all transplants are performed for the
diagnosis FSGS
12-24% of pediatric ESRD patients have FSGS as
diagnosis
Heavy proteinuria, hypertension and interstitial
fibrosis are risk factors for rapid loss of renal
function
Progression to ESRD in 2 years
SRNS- Mendoza Protocol
Week
1-2
3-10
11-18
Methyprednisolone
Dose 30 mg/kg
3x/week
1x/week
1x every 2weeks
Number
Pulses
6
8
4
19-50
51-82
1x every 4 weeks
1x every 8 weeks
8
4
Prednisone
0
2 mg/kg qOD
With or without
taper
Slow taper
Slow taper
Alkylating agent added if complete or partial remission not
achieved by 2 weeks, or if Urine protein/creatinine ratio > 2
at 10 weeks
Cyclophosphamide 2-2.5 mg/kg/day for 8-12 weeks
Chlorambucil 0.18-0.22 mg/kg/day for 8-12 weeks
SRNS- Mendoza Protocol
Remission, Normal CrCl
Proteinuria
Urine p/c ratio 0.2-0.5
Urine p/c ratio 0.5-1.9
Urine p/c ratio >2.0
Renal Function
Proteinuria, normal CrCl
Decreased CrCl
ESRD
Number
21/32
%
66
3/32
2/32
6/32
9
6
19
3/32
5/32
3/32
9
16
9
SRNS- Cyclophosphamide
ISKDC Trial of SRNS (FSGS)
Prednisone 40 mg/m2 qOD x 12 months
Cyclophosphamide 2.5 mg/kg/day x 3 months plus
the same prednisone dose
Control 28% complete remission
Treatment group 25% complete remission
Geary- 12/29 patients full or partial response
Tejani reported 0/10 responded
SRNS- ACE Inhibition
Milliner reported a 50% decrease in
proteinuria without a decrease in GFR in
patients with SRNS treated with ACE I