This document discusses idiopathic nephrotic syndrome in children. It defines nephrotic syndrome and describes the most common types including minimal change disease, focal segmental glomerulosclerosis, congenital nephrosis, and membranoproliferative glomerulonephritis. It outlines the clinical features, pathogenesis, epidemiology, associations, complications, treatment with corticosteroids and diuretics, and prognosis of nephrotic syndrome in children.
Nephrotic syndrome made easy, it can help you a lot to learn the basics about Nephrotic Syndrome and for more information I recommend the Dr. Najeeb videos about nephrotic and nephritic syndrome.
Presented at Belfast City Hospital Physician's Meeting.
Topic - A case of Focal Segmental Glomerulosclerosis with all the complications of nephrotic syndrome and transplant recurrence of FSGS.
Steroid resistant nephrotic syndrome in children: Clinical presentation, rena...iosrphr_editor
The IOSR Journal of Pharmacy (IOSRPHR) is an open access online & offline peer reviewed international journal, which publishes innovative research papers, reviews, mini-reviews, short communications and notes dealing with Pharmaceutical Sciences( Pharmaceutical Technology, Pharmaceutics, Biopharmaceutics, Pharmacokinetics, Pharmaceutical/Medicinal Chemistry, Computational Chemistry and Molecular Drug Design, Pharmacognosy & Phytochemistry, Pharmacology, Pharmaceutical Analysis, Pharmacy Practice, Clinical and Hospital Pharmacy, Cell Biology, Genomics and Proteomics, Pharmacogenomics, Bioinformatics and Biotechnology of Pharmaceutical Interest........more details on Aim & Scope).
Nephrotic syndrome made easy, it can help you a lot to learn the basics about Nephrotic Syndrome and for more information I recommend the Dr. Najeeb videos about nephrotic and nephritic syndrome.
Presented at Belfast City Hospital Physician's Meeting.
Topic - A case of Focal Segmental Glomerulosclerosis with all the complications of nephrotic syndrome and transplant recurrence of FSGS.
Steroid resistant nephrotic syndrome in children: Clinical presentation, rena...iosrphr_editor
The IOSR Journal of Pharmacy (IOSRPHR) is an open access online & offline peer reviewed international journal, which publishes innovative research papers, reviews, mini-reviews, short communications and notes dealing with Pharmaceutical Sciences( Pharmaceutical Technology, Pharmaceutics, Biopharmaceutics, Pharmacokinetics, Pharmaceutical/Medicinal Chemistry, Computational Chemistry and Molecular Drug Design, Pharmacognosy & Phytochemistry, Pharmacology, Pharmaceutical Analysis, Pharmacy Practice, Clinical and Hospital Pharmacy, Cell Biology, Genomics and Proteomics, Pharmacogenomics, Bioinformatics and Biotechnology of Pharmaceutical Interest........more details on Aim & Scope).
4. 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
5. 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
6. 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.
7. 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%
8. 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)
9. 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
10. 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
11. 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
12. 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
13. 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
15. 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
16. 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
17. Clinical Features- Edema
Physical exam
Accumulates in gravity dependent tissues
Puffiness around eyes
Genital edema is generally painful
18. 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
19. 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 3-
4% 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.
20. 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.
27. 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
31. 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
33. 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%
34. 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.
36. 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
39. 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.
42. 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
43. 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
45. 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)
46. 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
50. 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
51. Options for Alternative Therapy-
SSNS
Alkylating Agents
Nitrogen mustard
Cyclophosphamide
Chlorambucil
Levamisole
Cyclosporine
52. 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
53. 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
55. 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
56. Cyclosporine- SSNS
5 mg/kg/day
Used with steroids
Patients usually respond well
Cyclosporine dependence is common
Long term side effects unknown
57. 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
58. SRNS- Mendoza Protocol
Week Methyprednisolone
Dose 30 mg/kg
Number
Pulses
Prednisone
1-2 3x/week 6 0
3-10 1x/week 8 2 mg/kg qOD
11-18 1x every 2weeks 4 With or without
taper
19-50 1x every 4 weeks 8 Slow taper
51-82 1x every 8 weeks 4 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
59. SRNS- Mendoza Protocol
Number %
Remission, Normal CrCl 21/32 66
Proteinuria
Urine p/c ratio 0.2-0.5 3/32 9
Urine p/c ratio 0.5-1.9 2/32 6
Urine p/c ratio >2.0 6/32 19
Renal Function
Proteinuria, normal CrCl 3/32 9
Decreased CrCl 5/32 16
ESRD 3/32 9
60. 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
61. SRNS- ACE Inhibition
Milliner reported a 50% decrease in
proteinuria without a decrease in GFR in
patients with SRNS treated with ACE I
