Steroid therapy is the mainstay of the
treatment of NS in children. Standard regime is as follows:
Oral prednisolone 2 mg/kg/day or 60 mg/m2 /day -bid/tid for 4-6 weeks, followed by 1.5 mg/kg or 40 mg/m2 on alternate days as a single dose for 4-6 weeks.
Remission is defined as urinary albumin absent/trace on 3-4 consecutive days. Good response is achieved in 93-95% of minimal change NS in initial episode, whilst non-minimal changes respond poorly. Those who fail to respond to standard 4 weeks' daily steroid therapy are steroid - resistant cases and they should undergo kidney biopsy to classify them under appropriate histological diagnosis which helps in future planning of therapy.
Steroid therapy for the initial or first attack should be started as follows:
Oral prednisolone 2mg/kg/day in 2-3 divided doses after food is given for 4 - 6 weeks daily. Urine should be tested for albumin and recorded in a diary every day till protein in urine reduces to nil or trace for 3 - 4 days. Steroid response is achieved in 10-15 days during which daily weight, B.P and urine output should be recorded. Decrease in weight (edema), increase in urine output with maintenance of normal BP is associated with a good response and child may be treated on OPD basis. After 4 weeks, the child may show moon facies or mild elevation of BP while on daily dose of steroids, hence weekly BP, weight, clinical examination along with urine test for proteinuria is essential till the course of steroids is completed.
After 4-6 weeks of daily oral prednisolone therapy, the dose is reduced to 1.5mg/kg as a single dose on alternate day or every 48 hours for 4-6 weeks. During the alternate day therapy, weekly weight, BP, urine examination (to ensure that proteinuria is controlled) should be continued.
If there are no side effects of steroid therapy like high BP, striae, Cushingoid facies, myopathy, infections, abdominal pain due to gastritis, reduced dose of oral prednisolone (1mg/kg) on alternate days is advised for 4 more weeks in the treatment of initial episode of nephrotic syndrome. Intensive therapy of the first attack is known to reduce the risk of future relapse of Nephrotic syndrome.
- Frequent relapses/ steroid dependent cases
Major therapeutic challenges in NS
- Steroid resistant cases
These 2 types of nephrotic syndrome are designated as "difficult nephrotics " because of need to use alternative therapy, repeated and prolonged steroid therapy causing serious side effects, increased risk of life, threatening infections, thrombosis,hypertension, drug toxicity and possibility of chronic renal failure in steroid - resistant cases. Difficult nephrotics should be managed by pediatric nephrologists, who are experienced in treating such cases.
Frequent relapsing/steroid dependent NS requires individualized approach. Regular examination of urine for heavy/nephrotic range proteinuria is the only method of diagnosing relapses and treatment should start when three consecutive urine samples show 2+ or more proteinuria, which is defined as a relapse. First, 2-3 relapses are treated with short courses of oral prednisolone i.e. 2 mg/kg/day till remission occurs followed by alternative days single dose for 4 weeks. Since repeated courses of high dose steroids cause more steroid toxicity than alternative day regimes given for 6-12 months, after the 3rd relapse within 6 months i.e. frequent relapser or steroid - dependent case is subsequently treated with oral prednisolone used in as low dose as possible on alternate days to maintain sustained remission without major side-effects. Most children tolerate 0.5 mg/kg of prednisolone on alternate days without side-effects and maintain protein-free urine.
Along with regular urine examination, side effects of steroids should be looked for, namely cushingoid facies, obesity, striae, hirsutism, acne, hypertension, susceptibility to infections, pancreatitis and if used for more than a year, post subcapsular cataract, growth retardation, myopathy and rarely, peptic ulceration and avascular necrosis of bone. Pubertal growth spurt may be delayed in boys.
Alternative drug therapy is indicated in a steroid responsive NS if:
- Relapse occurs on prednisolone dose > 0.5 mg/kg on alternative days with :
- Unacceptable side - effects.
- Boys approaching puberty or diabetes.
- Severe relapses with hypovolemia, thrombosis, sepsis or acute renal failure.
- Relapse on prednisolone dose > 1 mg/kg on alternate days.
- Drugs used for alternative therapy are introduced after inducing remission with oral prednisolone therapy whilst tapering steroids. The details for dosage, duration and side- effects of these drugs is given in Table 1.
Table 1:Drugs used for alternative therapy in steroid - dependent or frequently relapsing NS
Drug dosage and duration
Reversible - alopecia, Hemorrhagic cystitis, Bone Marrow suppression, Infections.
Long term - gonadal toxicity, sterility and malignancy.
Clinical: CBC, Urinalysis (every two weeks).
Sperm count after puberty.
Same as above
After puberty EEG.
2.5 mg/kg/alternate day
x 6 - 24 months
Skin rash, abdominal pain, vomiting and neutropenia.
Hypertension, gingival hyperplasia, hirsutism, hyperkalemia, infections, nephrotoxicity.
Drug monitoring monthly (Trough Level 100 - 150 ng/ml), S. Creatinine monthly.
Kidney biopsy yearly.
Check list prior to steroid therapyPresence of infection: Mantoux test, X-ray chest, CBC, urine culture, hepatitis B test. Steroids flare up the infections and in presence of infection steroids fail to give good response. Treatment of infection is advised before starting steroid therapy.
Severe edema with oliguria can be associated with hypovolemia (detected clinically by poor capillary fill and raised hematocrit and BUN), which requires IV Fluids before starting steroids; otherwise a nephrotic child can go into shock. Use of diuretics like furosemide is not advised in presence of hypovolemia or shock.
Presence of joint involvement, skin rash, anemia, and purpura are rare but when present demand attention to rule out systemic lupus erythematosus or Henoch Schonlein Purpura etc.
RelapseAfter completion of the treatment of first episode, weekly urine examination for proteinuria is advised for 1 month and subsequently every 2-4 weekly or whenever edema recurs. If urine shows proteinuria of 3+ to 4+ in 3-4 urine examinations in a week, a relapse is diagnosed. Many relapses occur with infections.
Treatment of relapse:
Look for focus of infection (throat, skin, urine etc) and treat with appropriate antibiotics e.g. Amoxycillin, Cephalexin etc for 6-7 days.
After 1 week if urine shows 3+/4+ protein after the infection is controlled, steroid therapy should be started as oral prednisolone 2mg/kg/day in 2 - 3 divided doses till 3 consecutive urine samples show absent or trace proteinuria, after which the dose of prednisolone is reduced to 1.5mg/kg as a single dose on alternate day for 4 weeks. If urine is cleared of proteins, steroid therapy is stopped.
If urine protein shows less than 2+ after control of infection, steroids should be withheld and child should be kept under close observation to detect presence of edema and proteinuria for next 2-3 weeks during which either proteinuria clears or increases to 3+ to 4 requiring steroids therapy for relapse.
Each relapse should be treated as above. If more than 2 relapse occur within 6 months after initial therapy, the child is diagnosed as frequent relapser.
The treatment of frequent relapsers or steroid dependent (relapse occurring while tapering steroids or within 2 weeks of stopping steroids) cases should be done by experienced pediatric nephrologist because this includes need for prolonged steroid therapy which is fraught with severe side effects; use of cytotoxic drugs like cyclophosphamide or chlorambucil and newer immunomodulatory drugs like levamisole or cyclosporin A. Severe life threatening infections like peritonitis, septicemia, meningitis etc. occur in frequent relapses.
All through the course of steroid therapy, the primary pediatrician should advise the parents as regards diet (salt restriction in edematous state, no need to increase protein in the diet), prevention of infections and immunizations (Chickenpox; Hib and pneumococcal vaccine are given 4 - 6 weeks after completion of steroid therapy; DPT can be given while tapering prednisolone dose but oral polio vaccine is given after stopping steroids for 1 - 2 months).
Even when the child is in remission i.e. no proteinuria regular follow up once every 4 - 12 weeks is required for at least 1 - 5 years before a child with nephrotic syndrome is said to be well controlled.
Good response to steroids is the best marker of good outcome and 75 - 80% nephrotic children with onset between 2 - 7 years respond to oral prednisolone therapy, do not require kidney biopsy (because minimal change N.S. is the commonest histologic diagnosis in this age group), continue to have renal function, normal B.P. and good quality of life.