Treatment of nephrotic syndrome in children
Confirming the Diagnosis of Nephrotic Syndrome.
The diagnosis of nephrotic syndrome is confirmed by urinalysis with first-morning urine protein: creatinine ratio and serum electrolytes, blood urea nitrogen, creatinine, albumin, and cholesterol levels; evaluation to rule out secondary forms of nephrotic syndrome (children ≥10 yr): complement C3 level, antinuclear antibody, double-stranded DNA and hepatitides B and C, and HIV in high-risk populations; and kidney biopsy (for children ≥12 yr, who are less likely to have MCNS).
The urinalysis reveals 3+ or 4+ proteinuria and microscopic hematuria is present in 20% of children.
A spot urine protein : creatinine ratio should be >2.0. The serum creatinine value is usually normal, but it may be abnormally elevated if there is diminished renal perfusion from contraction of the intravascular volume.
The serum albumin level is <2.5 g/dL and serum cholesterol and triglyceride levels are elevated. Serum complement levels are normal. A renal biopsy is not routinely performed if the patient fits the standard clinical picture of MCNS.
Treatment
Children with their first episode of nephrotic syndrome and mild to moderate edema may be managed as outpatients. Such outpatient management is not practiced in all major centers, because the time required for successful education of the family regarding all aspects of the condition can require a short period of hospitalization.
The child’s parents must be able to recognize the signs and symptoms of the complications of the disease and may be taught how to use a dipstick and interpret the results to monitor for the degree of proteinuria. Tuberculosis must be ruled out prior to starting immunosuppressive therapy with corticosteroids by placing a purified protein derivative or obtaining an interferon release assay, and confirming a negative result.
Children with onset of uncomplicated nephrotic syndrome between 1 and 8 yr of age are likely to have steroid-responsive MCNS, and steroid therapy may be initiated without a diagnostic renal biopsy.
Kidney biopsy should be considered before treatment for children who have characteristics that reduce the likelihood of MCNS (gross hematuria, hypertension, renal insufficiency, hypocomplementemia, or age 1 yr or >12 yr
The treatment guidelines for corticosteroid use presented below are adapted from and based on the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guidelines on glomerulonephritis.
Treatment of Initial Episode of Nephrotic Syndrome
In children with presumed MCNS, prednisone or prednisolone should be administered as a single daily dose of 60 mg/m2/day or 2 mg/kg/day to a maximum of 60 mg daily for 4-6 wk followed by alternate-day prednisone (starting at 40 mg/m2 qod or 1.5 mg/kg qod) for a period ranging from 8 wk to 5 mo, with tapering of the dose. When planning the duration of steroid therapy, the side effects of prolonged corticosteroid administration must be kept in mind. Approximately 80-90% of children respond to steroid therapy.
Response is defined as the attainment of remission within the initial 4 wk of corticosteroid therapy. Remission consists of a urine protein : creatinine ratio of <0.2 or <1+ protein on urine dipstick for 3 consecutive days. The vast majority of children who respond to prednisone therapy do so within the first 5 wk of treatment
Relapse of Nephrotic Syndrome.
Definition-urine protein : creatinine ratio of >2 or ≥3+ protein on urine dipstick testing for 3 consecutive days. Relapses are common, especially in younger children, and are often triggered by upper respiratory or gastrointestinal infections.
Treatment of relapse
Prednisolone 2 mg/kg per day daily (maximum 60 mg in single/ divided doses) for 4 weeks or remission whichever is earlier, followed by 1.5 mg/kg (maximum 40 mg) as a single morning dose on alternate days for the next 4 weeks and then therapy discontinued abruptly
The duration of alternate day therapy varies depending on the frequency of relapses of the individual child.
Children are classified as infrequent relapsers or frequent relapsers, and as being steroid dependent based on the number of relapses in a 12 mo period or their inability to remain in remission following discontinuation of steroid therapy.
Treatment of Frequent Relapsing Nephrotic Syndrome/ Steroid Dependent Nephrotic Syndrome:
FRNS/SDNS
Relapse is managed as mentioned above
On attaining remission, prednisolone is gradually tapered to maintain the patient in remission on alternate day dose
of 0.5-0.7 mg/kg, which is administered for 9-18 months. If the dose of prednisolone to maintain remission is higher/steroid toxicity features are seen, immunomodulatory drugs that act as steroid-sparing agents are used.
(a) Levamisolean antihelmintic agent with immunomodulating effects- 2-2.5 mg/kg on alternate days for 12-24 months co-treatment with prednisolone- 1.5 mg/kg on alternate days is given for 2-4 weeks; its dose is gradually reduced by 0.15-0.25 mg/kg every 4 weeks to a maintenance dose of 0.25-0.5 mg/kg that is continued for six or more months.
(b) Oral Cyclophosphamide-2-2.5 mg/kg/day for 12 weeks. Prednisolone is co-administered at a dose of 1.5 mg/kg
on alternate days for 4 weeks, followed by 1 mg/kg for the next 8 weeks; steroid therapy is tapered and stopped over the next 2-3 months.
The potential side effects of the drug (neutropenia, disseminated varicella, hemorrhagic cystitis, alopecia, sterility, increased risk of future malignancy) should be carefully reviewed with the family before initiating treatment
During cyclophosphamide therapy, the white blood cell count must be monitored weekly and the drug should be withheld if the count falls below 5,000/mm3. The cumulative threshold dose above which oligo- spermia or azoospermia occurs in boys is >250 mg/kg
(c) Calcineurin inhibitors: Cyclosporin (CSA) is given at a dose of 4-5 mg/kg daily for 12-24 months. Prednisolone
is co-administered at a dose of 1.5 mg/kg on alternate days for 2-4 weeks; its dose is gradually reduced by 0.15-0.25 mg/kg every 4 weeks to a maintenance dose of 0.25-0.5 mg/kg that is continued for six or more months. Tacrolimus is an alternative agent, administered at a dose of 0.1-0.2 mg/kg daily for 12-24months.
Children must be monitored for side effects, including hypertension, nephrotoxicity, hirsutism, and gingival hyperplasia.
d) Mycophenolate mofetil (MMF) is given at a dose of 800- 1200 mg/m² along with tapering doses of prednisolone for 12-24 months.
Steroid Resistance.
Steroid resistance is 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
-FSGS (80%),
-MCNS, or
– membranoproliferative glomerulonephritis.
Steroid-dependent patients, frequent relapsers, and steroid-resistant patients are candidates for alternative therapies, particularly if they have severe corticosteroid toxicity (cushingoid appearance, hypertension, cataracts, and/ or growth failure).
There are no data from randomized clinical trials directly comparing the various corticosteroid-sparing agents. Most children who respond to cyclosporine, tacrolimus, or mycophenolate therapy tend to relapse when the medication is discontinued.
Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers may be helpful as adjunct therapy to reduce proteinuria in steroid-resistant patients.
Immunizations in Children with Nephrotic Syndrome.
To reduce the risk of serious infections in children with nephrotic syndrome, give full pneumococcal vaccination (with the 13-valent conjugant vaccine and 23-valent polysaccharide vaccine) and influenza vaccination annually to the child and their household contacts; defer vaccination with live vaccines until the prednisone dose is below either 1 mg/kg daily or 2 mg/kg on alternate days.
Live virus vaccines are contraindicated in children receiving corticosteroid sparing agents such as cyclophosphamide or cyclosporine. Following close contact with varicella infection, give immunocompromised children on immunosuppressive agents varicella-zoster immune globulin if available; immunize healthy household contacts with live vaccines to minimize the risk of transfer of infection to the immunosuppressed child, but avoid direct exposure of the child to gastrointestinal or respiratory secretions of vaccinated con
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