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Nephrotic Syndrome in Children

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10.5005/jp-journals-10011-1333
Deepak Viswanath
REVIEW ARTICLE
Nephrotic Syndrome in Children
Deepak Viswanath
ABSTRACT
Nephrotic syndrome is a set of signs or symptoms that may
point to kidney problems. The kidneys are two-bean shaped
organs found in the lower back, each about the size of a fist.
They clean the blood by filtering out excess water and salt and
waste products from food. Healthy kidneys keep protein in the
blood, which helps the blood soak up water from tissues; but
kidneys with damaged filters may leak protein into urine. As a
result, not enough protein is left in the blood to soak up water.
A child with nephrotic syndrome has these signs:
• High levels of protein in urine, a condition known as proteinuria
• Low levels of protein in the blood
• Swelling as a result of excess build-up of salt and water
• Less frequent urination
• Weight gain from excess water.
Keywords: Children, Nephrotic syndrome, MCNS, FSGS,
Prednisolone.
How to cite this article: Viswanath D. Nephrotic Syndrome in
Children. J Indian Acad Oral Med Radiol 2013;25(1):18-23.
Source of support: Nil
Conflict of interest: None declared
INTRODUCTION
Nephrotic syndrome is a set of signs or symptoms that may
point to kidney problems. Both adults and children can have
nephrotic syndrome. The causes of and treatments for
nephrotic syndrome in children are sometimes different from
the causes and treatments in adults. Childhood nephrotic
syndrome can occur at any age but is most common between
the ages of 1 year 6 months and 5 years. It seems to affect
boys more than the girls.
Nephrotic syndrome is an important chronic disease in
children, characterized by minimal change disease in the
majority. Research on pathogenesis has emphasized the
importance of T lymphocyte dysregulation and vascular
permeability factors that alters podocyte function and
permselectivity. While mutations in genes that encode
important podocyte proteins have been identified,
a hypothesis unifying available evidence on pathogenesis
is yet to be proposed. Patients with nephrotic syndrome are
at risk for life-threatening infections and thromboembolic
episodes.
The estimated annual incidence of nephrotic syndrome
in healthy children is 2 to 7 new cases per 100,000 children
younger than 18 years of age, making it a relatively common
major disease in pediatrics. Approximately, 50% of affected
children are between the ages of 1 year 6 months and
5 years; 75% are younger than 10 years of age. In addition,
18
even the most benign form of nephrotic syndrome is, by
nature, a recurrent disorder, so each new onset case likely
will continue to manifest disease for some time.
Careful examination of the anatomy of a nephron permits
characterization of the glomerular basement membrane as
the barrier between the circulation and the external
environment. Thus, the glomerular membrane, which
permits passage in an adult of approximately 180 L/d of
fluid, is the final determinant of how much of the solute
originally contained in this volume enters the tubular lumen.
The normal glomerular membrane is remarkably selective
for protein compared with other solutes. Once this selectivity
is lost, the ensuing proteinuria defines not only the diagnosis
of nephrotic syndrome, but many pathophysiological
consequences as well. It is the purpose behind this article
to discuss the definition, causes, pathophysiologic
consequences, and management of nephrotic syndrome.
DEFINITION
A clinical syndrome characterized by heavy proteinuria,
hypoalbuminemia (albumin <25gm/dl), edema and
hypercholesterolemia.
Nephrotic syndrome may be primary:
• Minimal change nephrotic syndrome disease (MCNS)
• Focal segmental glomerulosclerosis (FSGS) or
secondary to systemic disease (e.g. lupus).
Nephrotic syndrome is a common chronic disorder,
characterized by alterations of permselectivity at the
glomerular capillary wall, resulting in its inability to restrict
the urinary loss of protein. Nephrotic range proteinuria is
defined as proteinuria exceeding 1,000 mg/m2 per day or
random urine protein-to-creatinine exceeding 2 mg/mg. The
proteinuria in childhood nephrotic syndrome is relatively
selective, primarily constituted by albumin. It occurs from
2 to 7 per 100,000 children, and prevalence from 12 to
16 per 100,000.1 It occurs more in children of south Asia2
where the condition is primary (idiopathic) in 95% of cases.
An underlying disorder that may be identified includes,
systemic lupus erythematosus, Henoch Schonlein purpura,
amyloidosis and HIV infection, parvovirus B 19 and
Hepatitis B and C viruses.1,3,4
Although the overall incidence of childhood idiopathic
nephrotic syndrome has been generally stable over the past
3 decades, 5 the histological pattern is changing. The
incidence of FSGS seems to be increasing, in adults and
children, even after treatment for changes in renal biopsy
 JIAOMR

Nephrotic Syndrome in Children

practises (Table 1). 6-9 Ethnic origin also affects the
histological variant and the response to immunosuppressive
treatment. In particular, Hispanics and blacks are most likely
to have steroid unresponsive nephrotic syndrome than
whites.10 Age at initial presentation also has an important
say on the disease distribution frequency, 70% of MCNS
patients are younger than 5 years; 20 to 30% of adolescent
patients have MCNS.11 FSGS develops in children around
6 years6 and during the first year of life, congenital and
infantile genetic disorders and congenital infections are
more common than MCNS and FSGS and not all cases of
MCNS or FCGS are idiopathic (Table 2).
Common definitions for defining the course of nephrotic
syndrome are listed in Table 3.
The role of podocyte proteins in the pathogenesis of
idiopathic nephrotic syndrome requires further investigation.
Genetic mutations have been identified in some children
with sporadic steroid-resistant nephrotic syndrome and in
particular, mutations have been identified in patients with
sporadic FSGS;23-25 mutations in WT-1 have been reported
in children with isolated diffuse mesangial sclerosis.26,27
Permeability Factor
The role of a systemic circulating factor has been
hypothesized in patients with MCNS and FSGS. The clinical
response toward immunosuppressive drugs and also lack
of inflammatory changes in renal parenchyma suggest an
extrarenal factor as causative agent for proteinuria. Various

PATHOGENESIS Table 2: Causes of childhood nephrotic syndrome

Primary Glomerular Defect • Genetic disorders

– Nephrotic-syndrome typical
The glomerular capillary wall consists of three structural - Finnish-type congenital nephrotic syndrome
- FSGS
elements that constitute the permselectivity barrier: - Diffuse mesangial sclerosis
endothelial cells separated by fenestrae, the glomerular - Schimke immuno-osseous dysplasia
– Proteinuria with/without nephrotic syndrome
basement membrane containing matrix proteins, and - Nail-patella syndrome
podocytes (specialized epithelial cells). Normally, larger - Alport’s syndrome
proteins (>69 kD) are excluded from filtration; but in – Metabolic disorders with/without nephrotic syndrome
- Fabry disease
nephrotic syndrome, glomeruli appear greatly changed, - Hurler’s syndrome
adjacent podocytes are fused together, assuming a foot-like - Lipoprotein disorders
morphology. - Sickle cell disease
- Mitochondrial cytopathies
Some observations provide important clues to the – Idiopathic nephrotic syndrome
primary pathophysiology of idiopathic nephrotic syndrome. - MCNS
- FSGS
Mutations in several podocyte proteins have been identified
- Membranous nephropathy
in families with inherited nephrotic syndrome; a plasma • Secondary causes
factor may alter glomerular permeability, especially in – Infections
- Hepatitis B, C
patients with steroid-resistant nephrotic syndrome and lastly - HIV-1
altered T-lymphocyte responses, in that the T-cells could - Malaria
result in the production of a permeability factor that can - Syphilis
– Drugs
interfere with the expression, function or both to cause - Penicillamine
proteinuria. - Gold
- Nonsteroidal anti-inflammatory drugs
Nephrin was the first slit-diaphragm protein
- Mercury
identified12-22 and mutations in this transmembrane protein - Heroin
cause congenital (Finnish-type) nephrotic syndrome that – Immunological or allergic disorders
- Bee sting
occurs with a frequency of 1 per 8,200 live births in Finland. - food allergens
Among children with inherited nephrotic syndrome, – Glomerular hyperfiltration
investigators have identified mutations in other genes that - Morbid obesity
- Oligomeganephronia
encode podocyte proteins.

Table 1: Increase in incidence of childhood nephrotic syndrome due to FSGS

ERA 1 ERA 2
Dates n (%) Dates n (%)
4
India Jan 1990-Jun 1992 65 (20) July 1992-Dec 1996 157 (47)
USA8 Before 1990 68 (23) After 1990 36 (47)
Saudi Arabia9 1983-92 132 (5) 1997-2001 46 (15)

Journal of Indian Academy of Oral Medicine and Radiology, January-March 2013;25(1):18-23 19

Deepak Viswanath

vascular permeability factors have been implicated including
vascular endothelial growth factor, heparanase and
hemopexin.28 Vascular endothelial growth factor is a potent
permeability factor produced in vivo by normal glomerular
podocytes, and receptors for the factor are located on
glomerular endothelial and mesangial cells. Heparanase is
postulated to increase the permeability of glomerular
capillary wall by degrading heparin sulfate glucosamino-
glycans. One permeability factor that has received a lot of
attention was first identified in plasma of FSGS patients by
Savin and Sharma.29 This factor exerts permeability changes
in cultured rat glomeruli and is associated with a substantial
risk of recurrence of FSGS in a renal allograft.
Immunological Basis
Recent knowledge shows that antigen presentation to
T-lymphocytes results in a polarized immune response,
which may be type I (dominated by gamma interferons,
interleukin-2) or type II (IL-4, IL-10, or IL-13). Type I
cytokines predominate in cell-mediated immunity and
type II in humoral immunity and are particularly associated
with atopy and class switching of B cells for production of
IgG4 and IgE.30 The findings of increased plasma levels of
IgE, IgG4 and association with atopy suggest type II
cytokine bias in patients with MCNS. Further increased
systemic production of representative cytokines, chiefly
IL-4 is also reported. 31 In vitro studies suggest that
podocytes express receptors for IL-4 and IL-13.31 Activation
of these receptors, by respective cytokines, might disrupt
glomerular permeability resulting in proteinuria.
COMPLICATIONS
The chief complications of nephrotic syndrome is infection,
followed by thromboembolic events. Hypertension,
hyperlipidemia, features of corticosteroid toxicity and
behavioral disorders are less frequent.32
Infections: Increased predisposition to infections occur due
to loss of immunoglobulins, complement and prosperdin,
altered T-cell functions, immunosuppressive therapy and
presence of edema. Peritonitis, has an incidence of 2 to 6%,1
other common infections include cellulitis, pneumonias and
upper respiratory viral infections.33 Varicella and pneumo-
coccal vaccination is recommended for all children with
nephrotic syndrome once they are in remission and off
steroid therapy.3,34
Embolism: Patients with nephrotic syndrome are at an
increased risk for arterial and venous thrombosis, 35
additional predisposing factors include volume depletion,
infections, diuretic use, venepuncture and immobilization.35
Patients with clinical and radiological evidence of
thrombosis are initially treated with heparin or low
molecular weight heparin; the latter is preferred because it
is more effective and also convenient to administer.
Presently, they are no longer in use.
Hyperlipidemia: In most patients is transient and does not
have long-term implications.3 However, raised blood levels
of lipids may persist in patients with steroid resistant
nephrotic syndrome and potentially contribute to
cardiovascular morbidity and glomerulosclerosis.36 Patients
are advised to achieve a normal weight to height ratio, and
diet should be restricted in saturated fats.
Osteoporosis: The risk of steroid-induced osteoporosis has
significant long-term implications. A prospective study from
India37 showed that 22 of 100 patients with nephrotic
syndrome had features suggestive of low bone mass. Factors
predictive of low bone mass were older age at onset, low
calcium intake and cumulative steroid dosage.37 Leonard
et al38 examined the bone mineral content in 60 children
with nephrotic syndrome and 195 controls, and showed that
while the bone mineral content of the spine was lower
in patients, the whole body mineral content was higher
than controls.
DIAGNOSIS
Once diagnosed, a series of questions should be asked to
establish a cause for the nephrotic syndrome (Table 2). Since
MCNS is by far the most common cause of nephrotic
syndromes in childhood, initial efforts are devoted to the
detection of features that are similar to MCNS. A course of
corticosteroid treatment without a renal biopsy is indicated
for children without atypical features, since responsiveness
to steroids is a better indicator than kidney histology of long-
term prognosis for renal function.
Renal biopsy is done when there is poor or no response
of the initial episode after 4 to 6 weeks of standard treatment

Table 3: Common definitions to define the course of nephrotic syndrome

• Nephrotic syndrome Edema; nephrotic range proteinuria (>40 mg/m2/hr on timed sample); hypoalbuminemia (<2.5 g/dl)
• Relapse Urinary protein excretion >40 mg/m2/hr
• Remission Urinary protein excretion <40 mg/m2/hr
• Frequent relapses 2 or more relapses in 6 months of initial response
• Steroid dependence 2 consecutive relapses during steroid therapy
• Steroid resistance Failure to achieve remissions after 4 weeks of prednisolone therapy

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 JIAOMR

Nephrotic Syndrome in Children

(defined as steroid-resistant disease), and the child should
be medically stable. The biopsy is essential to distinguish
the nature and severity of the glomerular process, which
may be primary or secondary. Because proteinuria and
microscopic hematuria are injury responses of the
glomerulus, the need for clarification through renal biopsy
is plain. The indications for initial renal biopsy in the
nephrotic syndrome are summarized in Table 4.
Technological developments in ultrasonography have
reduced significantly the risk associated with percutaneous
renal biopsy in children. Moreover, the improvements in
electron microscopy equipment and technique, have
enhanced the ability of the histopathologist to interpret the
specimen accurately. Nonetheless, a renal biopsy is not
always essential to good medical care, and its use should
be viewed judiciously in all patients.
TREATMENT
Treatment of Initial Presentation of
Nephrotic Syndrome
indication for intravenous albumin. If there is evidence of
hypovolemia, give 1 gm/kg 20% albumin (5 ml/kg) over
4 to 6 hours. Give 2 mg/kg of IV furosemide midinfusion.
If clinically shocked, give 10 ml/kg 4.5% albumin. Children
should be closely monitored during albumin infusions, and
where possible should be administered during working hours.
Penicillin prophylaxis: Penicillin V can be given during
proteinuria and discontinued when the child goes into
remission. Grossly edematous children are at risk of cellulitis
and may benefit from antibiotic prophylaxis.
Dose: Under 5 years—125 mg bid and for above 5 years
250 mg bid.
Salt/Fluid restriction: A low salt diet is used to prevent
further fluid retention and also edema. Fluid restriction may
also be helpful.
Vaccination: Pneumococcal vaccination is recommended
for children with nephrotic syndrome. Varicella vaccination
is only available on a named patient basis.

Prednisolone: When the diagnosis of nephrotic syndrome
has been made, prednisolone can be started in children with
typical features; for children with atypical features, they
should be referred to pediatric nephrology for consideration
of renal biopsy.39 There is increasing evidence that longer
initial course of prednisolone are associated with a lower
incidence of relapse, and therefore a 12 weeks initial course
is recommended. The dosage of prednisolone is based on
the surface area.
• 60 mg/m2/day for 4 weeks (maximum 80 mg)
• 40 mg/m2/on alternate days for 4 weeks (maximum
60 mg)
• Reduce dose by 5 to 10 mg/m2 each week for another
4 weeks then stop.
Prednisolone can be given as a single dose in the
morning with food, or as divided doses during the day,
and patients have to be issued a steroid warning.
Albumin: Is indicated in clinical hypovolemia and
symptomatic edema. A low serum albumin is not an
Treatment of Relapse Nephrotic Syndrome
Upto 60 to 70% of children with nephrotic syndrome may
have one or more relapse. These are diagnosed if there is
+++ or ++++ proteinuria for 3 or more days. Urine should
be checked initially twice weekly, then weekly after the
first episode, and the families should be instructed to get in
contact in case a relapse of proteinuria occur, or if there is
++ for more than 1 week.
Prednisolone: Should be restarted once a relapse has been
diagnosed:
• 2 mg/kg daily (maximum 80 mg) until the urine is
negative or trace for 3 days.
• 40 mg/m2/on alternate days for 4 weeks (maximum
60 mg) then stop or taper the dose over 4 to 8 weeks.
Albumin: The indications are similar as for initial
presentation.
Salt/Fluid restriction: During proteinuria, no salt diet is
advised.

Table 4: Indications for initial renal biopsies in nephrotic syndrome

1. Patients having steroid-resistant nephrotic syndrome and continue to have proteinuria despite a full course of prednisolone
2. Patients having steroid-responsive nephrotic syndrome and have more than two relapses in a 6-month period (also called ‘frequent
relapsers’)
3. Patients who have a low serum complement at the time of initial presentation of nephrotic syndrome. Biopsy is indicated to rule out
hypocomplementemic membranoproliferative glomerulonephropathies
4. Nephrotic syndrome with hypertension at presentation; the risk of FSGS is higher
5. Patients younger than 1 year of age at presentation. Biopsy is indicated because of a high likelihood of congenital nephrotic
syndrome
6. Patients older than 10 years of age at presentation. Biopsy is indicated to rule out more serious pathology than minimal-change
disease
7. Systemic lupus erythematosus with proteinuria or nephrotic syndrome
8. Evidence of chronic renal insufficiency with persistent elevation of serum urea nitrogen and creatinine

Journal of Indian Academy of Oral Medicine and Radiology, January-March 2013;25(1):18-23 21

Deepak Viswanath
Penicillin prophylaxis: During proteinuria, penicillin can
be given.
Vaccination: Consider giving varicella vaccine between
relapses in children who are varicella seronegative.
Referral to pediatric nephrology in cases of:
• Frequent relapsers
• Steroid dependency
• Steroid toxicity.
Diagnosis and Treatment of Frequent Relapses
Frequent relapsers are diagnosed if there is:
• 2 or more relapses within the first 6 months of
presentation
• 4 or more relapses within any 12-month period.
This becomes steroid dependency. If the relapses are
occurring during steroid tapering, varicella status should
be repeated 6 monthly in those who are nonimmune.
Low dose alternate day prednisolone: In the dose of
10 to 15 mg/alternate days may prevent relapses.
Levamisole: Levamisole may be beneficial for children who
have occasional relapses. It is less useful for children who
are steroid dependent. The dose is 2.5 mg/kg on alternate
days for 6 months to a year. Reversible neutropenia is rare
but occurs sometimes, and a FBC should be checked
monthly for the first 3 months.
Cyclophosphamide: Can be given in the dose of 3 mg/kg/
day for 8 weeks.
Cyclosporin: At a dose of 2.5 mg/kg bid usually for 1 year
may be useful as a steroid sparing agent. Levels should be
checked after 1 to 2 weeks. For children under 5 years, tid
dosing may be necessary. Monitor BP and renal function.
Mycophenolate mofetil (MMF): Can be given to children
showing signs of cyclosporin toxicity. Doses of 600/m2/bid
have been used. FBC should be monitored for leukopenia.
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Nephrotic Syndrome in Children
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ABOUT THE AUTHOR
Deepak Viswanath
Professor, Department of Pedodontics and Preventive Dentistry
Krishnadevaraya College of Dental Sciences, Bengaluru, Karnataka
India, e-mail: pedodons@gmail.com
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