2. DEFINITION
Nephrotic syndrome is the clinical manifestation of
glomerular diseases associated with heavy (nephrotic-
range) proteinuria.(40mg/m2/hr or 50mg/kg/24hr)
The triad of clinical findings associated with
nephrotic syndrome arising from the large urinary losses
of protein are hypoalbuminemia (≤2.5 g/dL), edema,
and hyperlipidemia(cholesterol >200 mg/dL).
3. CLASSIFICATION
ETOLOGICAL CLASSIFICATION
Primary nephrotic syndrome: (90 %)
Disease limited to kidney
Not associated with a systemic disease
Secondary nephrotic syndrome(10%) – associated with
systemic disease such as HSP,SLE, amyloidosis.
Children with primary NS are also classified according to
their response to steroid therapy as
steroid sensitive or steroid-resistant.
4. HISTOLOGICAL CLASSIFICATION:
Primary NS or idiopathic nephrotic syndrome includes four
histological patterns:
1. Minimal change glomerular disease(MCD) (85%)
2. Diffuse mesangial proliferation (DMP)
3. Focal and segmental glomerulosclerosis(FSGS)
4. MCD or DMP associated with IgM deposits in the
mesangium
5. PATHOPHYSIOLOGY
Complex disturbances in
immune system
Genetic mutation / mutation in
proteins
Extensive effacement of podocyte
foot processes
Increased permeability of
glomerular basament membrane
Massive proteinuria
Decreased osmotic pressure and
increased hydrostatic pressure in
capillaries
Hypoalbuminemia
6. Edema
Decreased circulatory blood volume -
hypovolemia
Increased RAS activity
Increased sodium and water reabsorption
Hemo concentration
Increased ADH due to osmoreceptor
stimulation
Increased water retention
Worsening of
edema
7. Hypoalbuminemia
Increased protien synthesis by liver
along with excessive production of
lipids and fibrinogen
Hyper lipidemia
Lipiduria- lipid casts in
urine
hypercoagulability
Urinary loss of
coagulation
factors
8.
9. INVESTIGATIONS
TO CONFIRM DIAGNOSIS:
Urine analysis:
Nephroticrange proteinuria-
Urinary dipstick showing 3 + / 4+ protein
Urine protein : creatinine ratio >2
Proteinuria- 40mg/m2/hr,
24 hour urine 50mg/kg/24 hr
Selective proteinuria seen in Minimal change NS
RBC may be present in NS with significant
lesions(MPGN,FSGS)
13. SPECIFIC TREATMENT
Treatment of the Initial Episode:
Adequate treatment of the initial episode, both in terms of
dose and duration of corticosteroids is important.
Medication: The standard medication for treatment is
prednisolone or prednisone
14. Treatment regimen:
Initial episode of nephrotic syndrome treated with
prednisolone@ 2mg/kg/day(max of 60mg)in single or
divided doses for 6 weeks.
f/b
1.5 mg/kg(max of 40 mg)as a single dose for next 6 weeks
15. Remission: Urine albumin nil or trace (or proteinuria <4
mg/m2/h) for 3 consecutive early morning specimens.
Relapse: Urine albumin 3+ or 4+ (or proteinuria >40 mg/m2/h)
for 3 consecutive early morning specimens,having been in
remission previously.
Frequent relapses: Two or more relapses in initial six months
or more than three relapses in any twelve months.
Steroid dependence: Two consecutive relapses when on
alternate day steroids or within 14 days of its discontinuation.
Steroid resistance: Absence of remission despite therapy with
daily prednisolone at a dose of 2 mg/kg per day for 8 weeks.
16. Treatment of relapse:
The patient should be examined for infections, which
should be treated before initiating steroid therapy.
Prednisolone is administered at a dose of 2 mg/kg/day
(single or divided doses) until urine protein is trace or
nil for three consecutive days.
Subsequently, prednisolone is given in a single morning
dose of 1.5 mg/kg on alternate days for 4 weeks, and
then discontinued.
The usual duration of treatment for a relapse is thus 5-6
weeks.
In case the patient is not in remission despite two weeks
treatment with daily prednisolone, the treatment is
extended for 2 more weeks.
Patients showing no remission despite 4 weeks’ treatment
with daily prednisolone should be referred for evaluation.
17. Infrequent relapsers:
Patients who have three or less relapses a year and respond
promptly to prednisolone are managed using the
aforementioned regimen for each relapse.
Such children are at a low risk for developing steroid
toxicity
18. Frequent relapsers and steroid dependence:
Following induction of remission, the dose of prednisolone
is tapered gradually to maintain the patient in remission on
alternate day dose of 0.5 mg/kg or lower
Alternate day prednisolone may be administered for 9-18
months.
A close monitoring of growth and blood pressure, and
evaluation for features of steroid toxicity is essential.
If the prednisolone threshold, to maintain remission, is
higher than 0.5 mg/kg on alternate days, the following
immunomodulators are recommended.
19. (a) Levamisole- may be administered in a dose of 2 -2.5
mg/kg on alternate days for 12- 24 months
Treatment with prednisolone-1.5 mg/kg on alternate days,
is continued.
The dose of prednisolone is gradually reduced by 0.15-0.25
mg/kg every 4 weeks to a maintenance dose of 0.25 mg/kg,
which may be continued for six months.
The chief side effect of treatment with levamisole is
leukopenia
flu-like symptoms and skin rash may occur rarely.
The total leukocyte count should be monitored every 4-8
weeks
20. b)cyclophosphamide (2 mg/kg/day) may be
administered along with alternate day prednisolone (1-
1.5 mg/kg) for 12 weeks.
In view of safer toxicity profile, cyclophosphamide is
usually preferred
The total leukocyte count should be monitored every
2-3 weeks and treatment is discontinued if leukocyte
count falls below 4000/mm3.
Treatment with cyclophosphamide may rarely cause
alopecia, nausea and vomiting.
Treatment with cyclophosphamide may be considered
in patients showing: (i) significant steroid toxicity, (ii)
severe relapses with hypovolemia or thrombosis, and
(iii) poor compliance or follow up.
21. Steroid resistant nephrotic syndrome:
Defined as the failure to achieve remission after 8 wk of
corticosteroid therapy.
Children with steroid-resistant nephrotic syndrome require
further evaluation,including a diagnostic kidney biopsy,
evaluation of kidney function, and quantitation of urine
protein excretion (in addition to urine dipstick testing).
Steroid-resistant nephrotic syndrome is usually caused by
FSGS (80%), MCNS, or membranoproliferative
glomerulonephritis.
SRNS and specifically FSGS, is associated with a 50% risk
for end-stage kidney disease.
22. Calcineurin inhibitors (cyclosporine or tacrolimus) are
recommended as initial therapy for children with
steroid-resistant nephrotic syndrome.
Cyclosporine - administered in a dose of 4-5 mg/kg daily for
12-24 months.
Therapy is continued with prednisolone in a dose of 1.5
mg/kg on alternate days for 4 weeks, and then tapered
gradually
Side effects:- hypertension, gum hypertrophy and
hirsutism may occur, in which case the dose of cyclosporine
may be reduced to 3 mg/kg/day
23. Tacrolimus :
Is an alternative agent, administered at a dose of 0.1-0.2
mg/kg daily for 12-24 months.
Side effects include hyperglycemia, diarrhea and rarely
neurotoxicity (headache,seizures).
Blood levels of creatinine and glucose should be estimated
every 2-3 months.
24. Mycophenolate mofetil(mmf):
Is given at a dose of 800-1200 mg/m2 along with tapering
doses of prednisolone for 12-24 months.
side effects include gastrointestinal discomfort, diarrhea
and leukopenia.
Leukocyte counts should be monitored every 1-2 months
treatment is withheld if count falls below 4000/mm3.
The lack of renal,hemodynamic and metabolic toxicity
with this agent makes it an attractive alternative to
calcineurin inhibitors.
25.
26. The advantages of using these drugs should be balanced against
their potential toxicity.
Levamisole has a weak steroid sparing effect and is useful in
milder cases
Treatment with cyclophosphamide may be considered in
patients showing:
(i) significant steroid toxicity
(ii) severe relapses with hypovolemia or thrombosis
(iii) poor compliance or follow up.
Cyclosporin is recommended for patients that continue to show
steroid dependance or frequent relapses despite a course of
levamisole and cyclo-phosphamide.
28. DIET
A balanced diet adequate in protein and calories is
recommended.
The child should receive 1.5-2 g/kg of proteins.
Patients with persistent proteinuria are prone to mal-
nutrition and should receive 2-2.5 g/kg of protein daily.
29. Salt restriction is not necessary in most patients with
steroid responsive nephrotic syndrome.
Corticosteroids stimulate the appetite, and advice should
be given about ensuring physical activity and preventing
excessive weight gain.
30. EDEMA
Control of edema is an integral part of supportive care.
Since treatment with corticosteroids usually leads to diuresis
within 5-10 days, diuretics are avoided unless edema is
significant.
Patients with persistent edema and weight gain of 7-10% are
treated with oral frusemide (1-3 mg/kg daily).
Additional treatment with potassium sparing diuretics is not
required if frusemide is used at this dose for less than one week.
31. Patients requiring higher doses and prolonged duration of
treatment with frusemide should receive potassium sparing
diuretics, e.g., spironolactone (2-4 mg/kg daily).
Blood pressure should be monitored frequently.
A gradual reduction of edema, over one week, is preferred
Edema not responding to the above therapy should be
managed in a hospital.
32. For patients with refractory edema, a combination of
diuretics and albumin infusion is used.
Albumin (20%) is given as an infusion at a dose of 0.5-1
g/kg over 2-4hr, followed by administration of frusemide
(1-2 mg/kg IV)
While infusion of albumin results in increased urine
output, the effect is not sustained and repeated
administration might be necessary.
Patients receiving albumin should be observed for
respiratory distress, hypertension and congestive heart
failure.
33. PATIENT AND PARENT EDUCATION
A proportion of patients, especially those
(i) with early onset of nephrotic syndrome
(ii) with a frequently relapsing course
(iii) requiring treatment with alkylating agents or
Cyclosporine may continue to show relapses beyond
adolescence
Parental motivation and involvement is essential in the
long-term management of these children.
34. They should be provided information about the disease, its
expected course and risk of complications and the
following are emphasized:
(a)Urine examination for protein at home using dipstick,
sulfosalicylic acid or boiling test.
The examination should be done every morning during a
relapse, during intercurrent infections or if there is even
mild periorbital puffiness.
The frequency of urine examination is reduced, to once or
twice a week, before development of significant edema is
stressed.
35. (b) Maintain a dairy showing results of urine protein
examination, medications received and intercurrent
infections.
(c) Ensure normal activity and school attendance
(d) Since infections are an important cause of morbidity,
patients should receive appropriate immunization and other
measures for protection.
36. OTHER MEDICATIONS
The use of antacids or histamine receptor antagonists
is not necessary unless there are symptoms of upper
gastrointestinal discomfort.
Patients with steroid sensitive nephrotic syndrome do not
usually require medications for hyperlipidemia, since lipid
normalize following remission.
37. IMMUNIZATION
Parents should be advised regarding the need for
completing the primary immunization.
Administration of some vaccines, e.g., hepatitis B,MMR or
meningococcal vaccines may rarely precipitate a relapse.
Patients receiving prednisolone at a dose of 2 mg/kg/day or
greater, or total 20 mg/day or greater for more than 14 days
are considered immunocompromised, such patients should
not receive live attenuated vaccines but inactivated or
killed vaccines are safe.
38. All children with nephrotic syndrome should receive
immunization against pneumococcal infections.
Immunization Committee of the IAP recommends 2-4
doses of pneumococcal vaccine for children below 2 yr of
age.
For previously unimmunized children between 2-5 yr old, a
priming dose of the vaccine should be given 8 weeks later.
Children older than 5 yr require only a single dose of the
vaccine.
39. Revaccination after 5 yr is considered for children (<10-yr-
old) with active nephrotic syndrome.
Patients in remission and not on immunosuppressive
therapy should receive the varicella vaccine.
One dose is recommended for children between 12 months
and 12 yr of age, and 2 doses separated by an interval of
atleast 4 weeks for children 13 yr or older
40. KIDNEY BIOPSY
Performed before therapy with calcineurin inhibitors.
A biopsy is required to identify the underlying renal
disease in certain cases.
INDICATIONS
• Age of onset <1 year.
• Gross hematuria, persistent microscopic hematuria or low
serum C3.
• Sustained hypertension.
• Renal failure not attributable to hypovolemia.
• Suspected secondary causes of nephrotic syndrome.
• Proteinuria persisting despite 4-weeks of daily
corticosteroid therapy.
• Before treatment with cyclosporin or tacrolimus
41. COMPLICATIONS
Patients with steroid sensitive nephrotic syndrome are at risk
for certain complications, early detection of which is
necessary.
Infections
Thrombosis
Hypovolemia
Hypertension
Corticosteroid side effects
42. INFECTIONS
Common infections include peritonitis,cellulitis and
pneumonia.
Viral and bacterial infections may occasionally precipitate
relapses in patients previously in remission.
Varicella may be a severe illness in patients with nephrotic
syndrome receiving corticosteroids or other
immunosuppressive drugs.
43. Susceptible patients (those unimmunized or with no
history of varicella) who are exposed to a case of
chickenpox should therefore receive a single dose of
varicella zoster immunoglobulin, within 96 hr of exposure
to prevent or lessen the severity of the disease.
Since, this preparation is expensive and not easily available,
a single dose of intravenous immunoglobulin (400 mg/kg)
may be used .
Patients who develop varicella should receive intravenous
acyclovir (1500 mg/m2/day in 3 doses) or oral acyclovir (80
mg/kg/day in 4 doses) for 7-10 days.
44. The dose of prednisolone should be tapered to 0.5
mg/kg/day or lower during the infection.
Patients with nephrotic syndrome who are Mantoux
positive but show no evidence of tuberculosis should
receive prophylaxis with INH for six months.
Those showing evidence of active tuberculosis should
receive standard therapy with anti-tubercular drugs
47. THROMBOSIS
Children with nephrotic syndrome are at risk for venous
and, rarely, arterial thrombosis.
CAUSES:
Increased fibrinogen levels
Loss of antithrombin-iii,protein-c,protein-s
48. USG, Doppler studies and cranial MRI are useful in
confirming the diagnosis.
Patients with thrombotic complications require urgent
treatment.
The treatment includes correction of dehydration and
other complications, and use of heparin or low molecular
weight heparin (SC) initially, followed by oral
anticoagulants on the long term.
There is no role for prophylactic treatment with
anticoagulants in patients with hypoalbuminemia and
edema.
49. HYPERTENSION
This may be detected at the onset of nephrotic syndrome
or later due to steroid toxicity.
Therapy is initiated with ACE inhibitors, calcium channel
blockers or β adrenergic antagonists,keeping the blood
pressure at less than the 90th percentile
50. HYPOVOLEMIA
This complication can occur due to unsupervised use of diuretics
especially if accompanied by septicemia, diarrhea or vomiting.
The diagnosis is suggested by moderate to severe abdominal pain,
hypotension, tachycardia, cold extremities and poor capillary refill
Hematocrit and blood levels of urea and uric acid are elevated.
Management consists of rapid infusion of normal saline at a dose of
15-20 mL/kg over 20-30 minutes this is repeated if clinical features
of hypovolemia persist.
Infusion of 5% albumin (10-15 mL/kg) or 20% albumin (0.5-1 g/kg)
may be used in subjects who do not respond despite two boluses of
saline.
51. CORTICOSTEROID SIDE EFFECTS
Parents should be explained about the side effects of the
medications, including increased appetite, impaired
growth, behavioral changes, risk of infections, salt and
water retention, hypertension and bone demineralization.
All patients should be monitored for cushingoid features
and blood pressure; six-monthly record of height and
weight, and yearly evaluation for cataract should be done.
Patients on prolonged (>3 months) treatment with steroids
should receive daily supplements of oral calcium (250-500
mg daily) and vitamin D (125-250 IU).
52. REFERENCE
NELSON TEXTBOOK OF PEDIATRICS-FIRST SOUTH ASIA
EDITION.
NAMMALWAR MANUAL OF PEDIATRIC NEPHROLOGY.
INDIAN SOCIETY OF PEDIATRIC NEPHROLOGY CONSENSUS
STATEMENT ON MANAGEMENT OF NEPHROTIC SYNDROME-2008
INDIAN SOCIETY OF PEDIATRIC NEPHROLOGY CONSENSUS
STATEMENT ON MANAGEMENT OF STEROID RESISTANT
NEPHROTIC SYNDROME-2009
