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Table 4 Summary comparison between the three included clinical practice guidelines for management of steroid-sensitive nephrotic syndrome in children): Treatment

From: AGREEing on clinical practice guidelines for idiopathic steroid-sensitive nephrotic syndrome in children

Options of care and management of children with SSNS AAP CPG 2009 [25]
Moderate-quality CPG (Domain 3: 40–69%)
JSPN CPG 2014 [26,27,28]
High-quality CPG (Domain 3: ≥ 70%)
KDIGO CPG 2012 [29]
High-quality CPG (Domain 3: ≥ 70%)
Diet therapy Low-fat diet: limit dietary fat to < 30% of calories, saturated fat to < 10% of calories, and < 300 mg/day dietary cholesterol.
Low-sodium diet
(LoE: Not applicable, GoR: Opinion-based)
• Sodium restrictions for remission of edema (Not Graded)
• The degree of sodium restrictions should be determined based on the status of edema and amount of food intake.
• Base protein consumption on the nutrient requirement for healthy children of the same age
Base the caloric energy intake on the age of the patient
Not mentioned
Treatment of initial episode of SSNS with corticosteroids Prednisone 2 mg/kg per day for 6 weeks (maximum: 60 mg); then
Prednisone 1.5 mg/kg on alternate days for 6 weeks (maximum: 40 mg).
No steroid taper is required at the conclusion of this initial therapy. (LoE: Not applicable, GoR: Opinion-based)
ISKDC regimen: Prednisolone for 8 weeks (Grade B):
1. 60 mg/m2/day or 2.0 mg/kg/day in three divided doses daily for 4 weeks (maximum: 60 mg/day), followed by
2. 40 mg/m2 or 1.3 mg/kg once in the morning on alternate days for 4 weeks (maximum: 40 mg on alternate days).
Long-term, tapering regimen: prednisolone for 3–7 months
Oral prednisone or prednisolone as a single daily dose (1B) starting:
Daily: 60 mg/m2/day or 2 mg/kg/day to a maximum 60 mg/day (1D) for 4–6 weeks (1C)
then:
Alternate day: 40 mg/m2 or 1.5 mg/kg to a maximum 40 mg (1D) for 2–5 months with tapering of the dose (1B)
Treatment of relapsing SSNS with corticosteroids Prednisone 2 mg/kg per day until urine protein test results are negative or trace for 3 consecutive days; then
Prednisone 1.5 mg/kg on alternate days for 4 weeks
(LoE: Not applicable, GoR: Opinion-based)
Modified ISKDC regimen
1. 60 mg/m2/day or 2.0 mg/kg/day in three divided doses daily until confirmation of the resolution of proteinuria for at least 3 days but not exceeding 4 weeks (maximum: 60 mg/day), followed by
2. 60 mg/m2 or 2.0 mg/kg once in the morning on alternate days for 2 weeks (maximum: 60 mg on alternate days), followed by
3. 30 mg/m2 or 1.0 mg/kg once in the morning on alternate days for 2 weeks (maximum: 30 mg on alternate days), followed by
4. 15 mg/m2 or 0.5 mg/kg once in the morning on alternate days for 2 weeks (maximum: 15 mg on alternate days).
Long-term, tapering regimen
Should be selected when appropriate. (Not Graded)
Initially: Prednisone as a single daily dose 60 mg/m2 or 2 mg/kg (maximum: 60 mg/day) until the child has been in complete remission for at least 3 days (2D)
Then: Prednisone as a single dose on alternate days (40 mg/m2 per dose or 1.5 mg/kg per dose: maximum 40 mg on alternate days) for at least 4 weeks (2C)
Corticosteroid therapy in frequently relapsing (FR) and steroid-dependent (SD) SSNS in children Frequently relapsing SSNS
Prednisone 2 mg/kg/day until proteinuria normalizes for 3 days, 1.5 mg/kg on alternate days for 4 weeks, and then taper over 2 months by 0.5 mg/kg on alternate days (total: 3–4 months). (LoE: Not applicable, GoR: Opinion-based)
Steroid-dependent SSNS
Glucocorticoids are preferred in the absence of significant steroid toxicity.
Secondary alternatives should be selected based on risk/benefit ratio. (LoE: Not applicable, GoR: Opinion-based)
Use immunosuppressive agents (e.g., cyclosporine, cyclophosphamide) in the treatment of frequently relapsing and steroid-dependent nephrotic syndrome (Grade C1) due to the development of various steroid-induced side effects. Initially: daily prednisone until the child has been in remission for at least 3 days
Then: alternate-day prednisone for at least 3 months. (2C)
Long term steroid: prednisone to be given on alternate days in the lowest dose to maintain remission without major adverse effects. (2D) If not effective: daily prednisone at the lowest dose to be given to maintain remission without major adverse effects (2D)
Treatment of FR and SD SSNS with corticosteroid-sparing agents
Cyclophosphamide Frequently relapsing SSNS
Oral cyclophosphamide 2 mg/kg/day for 12 weeks (cumulative dose: 168 mg/kg) based on ideal body weight started during prednisone (2 mg/kg/day) induced remission, decrease prednisone dose to 1.5 mg/kg on alternate days for 4 weeks, and then taper over 4 weeks. (LoE: Not applicable, GoR: Opinion-based)
Steroid-dependent SSNS
Oral cyclophosphamide 2–3 mg/kg/day for 8–12 weeks.
Given the severity of cyclophosphamide-associated adverse events, cytotoxic agents are considered a third-line choice for steroid-dependent nephrotic syndrome therapy. (LoE: Not applicable, GoR: Opinion-based)
• To be given at an initial dose of 2–2.5 mg/kg/day (maximum: 100 mg) and then once daily for 8–12 weeks. (Grade C1)
• A second course of cyclophosphamide should not be given and that cumulative doses do not exceed 300 mg/kg.
Use: as corticosteroid-sparing agent. (1B) for FR and (2C) for SD SSNS
Dose: 2 mg/kg/day to be given for 8–12 weeks (maximum cumulative dose 168 mg/kg). (2C)
Timing: Not to be started until the child has achieved remission with corticosteroids. (2D)
Repeated courses: second courses of alkylating agents should not be administered. (2D)
Mycophenolate mofetil (MMF) Frequently relapsing SSNS
Mycophenolate mofetil 25–36 mg/kg/day (maximum: 2 g/day) in two divided doses for 1–2 years with a tapering dose of prednisone.
(LoE: Not applicable, GoR: Opinion-based)
Steroid-dependent SSNS
Mycophenolate mofetil 24–36 mg/kg/day or 1200 mg/m2/day in two divided doses (maximum: 2 g/day). (LoE: Not applicable, GoR: Opinion-based)
• To be considered when standard immunosuppressive agents cannot be used because of their side effects (Grade C1)
• A dose of 1000–1200 mg/m2/day or 24–36 mg/kg/day (maximum 2 g/day) be administered in two divided doses
Use: as corticosteroid-sparing agent (2C)
Dose: 1200 mg/m2/day in two divided doses (2C)
Duration: at least 12 months (2C)
Levamisole Use of levamisole may reduce the risk of relapses without glucocorticoids. (LoE: Not applicable, GoR: Opinion-based) Not mentioned Use: as corticosteroid-sparing agent. (1B)
Dose: 2.5 mg/kg on alternate days (2B)
Duration: at least 12 months (2C)
Cyclosporine Frequently relapsing SSNS
Cyclosporine A 3–5 mg/kg/day in two divided doses for an average of 2–5 years.
The nephrotoxic effects of cyclosporine warrant careful monitoring of kidney function and blood drug levels.
The risk for nephrotoxicity attributable to calcineurin inhibitors makes this a third line option for frequently relapsing nephrotic syndrome.
(LoE: Not applicable, GoR: Opinion-based)
Steroid-dependent SSNS
Cyclosporine A 3–5 mg/kg/day in two divided doses.
(LoE: Not applicable, GoR: Opinion-based)
To be given at an initial dose of 2.5–5 mg/kg/day in two divided doses, followed by dose adjustment according to monitoring of blood drug concentration (Grade C1) Use: as corticosteroid-sparing agent (1C)
Dose: 4–5 mg/kg/day in two divided doses. (2C)
Monitoring: Monitor CNI levels during therapy to limit toxicity. (Not Graded)
Duration: at least 12 months. (2C)
Mizoribine Use of mizoribine (not available in the USA) may reduce the risk of relapses without glucocorticoids.
(LoE: Not applicable, GoR: Opinion-based)
• Not administered at the standard dose (4 mg/kg/day, maximum 150 mg/day) as it would be inadequately effective. (Grade C1)
To be administered at higher doses of 7–10 mg/kg/day once daily, with a peak blood mizoribine concentration (C2*2 or C3*3) ≥ 3.0 μg/mL, because of reported efficacy in preventing relapses
Not to be used as corticosteroid sparing agent. (2C)
Tacrolimus Frequently relapsing SSNS
Tacrolimus, an alternative calcineurin inhibitor, provides no advantage regarding nephrotoxicity profile.
The risk for nephrotoxicity attributable to calcineurin inhibitors makes this a third-line option for frequently relapsing nephrotic syndrome.
(LoE: Not applicable, GoR: Opinion-based)
Steroid-dependent SSNS
Tacrolimus 0.05 to 0.1 mg/kg/day in two divided doses.
(LoE: Not applicable, GoR: Opinion-based)
• To be considered when cyclosporine cannot be used because of its cosmetic side effects.
Starting dose (0.1 mg/kg/day) should be administered in two divided doses, followed by dose adjustment according to monitoring of blood drug concentration
Use: To be used instead of cyclosporine when the cosmetic side effects of cyclosporine are unacceptable (as corticosteroid-sparing agent). (2D)
Dose: 0.1 mg/kg/day administered in two divided doses (2D)
Monitoring: Monitor CNI levels during therapy to limit toxicity. (Not Graded)
Duration: at least 12 months (2C)
Chlorambucil Frequently relapsing SSNS
Compared with cyclophosphamide, chlorambucil is associated with a slightly greater toxicity profile and no improvement in efficacy.
(LoE: Not applicable, GoR: Opinion-based)
Steroid-dependent SSNS:
Chlorambucil may reduce the risk of relapses without glucocorticoids.
(LoE: Not applicable, GoR: Opinion-based)
Not mentioned Use: as corticosteroid-sparing agent. (1B) for FR and (2C) for SD SSNS
Dose 0.1–0.2 mg/kg/day may be administered for 8 weeks (maximum cumulative dose 11.2 mg/kg) as an alternative to cyclophosphamide. (2C)
Repeated courses: second courses of alkylating agents should not be administered (2D)
Rituximab Not mentioned • To be considered only in refractory disease
• To be administered at a starting dosage of 375 mg/m2 per dose by intravenous drip infusion, administered one to four times (at 1-week intervals for multiple infusions) (Grade C1)
Use: to be considered only in children with SD SSNS who have continuing frequent relapses despite optimal combinations of prednisone and corticosteroid- sparing agents and/or who have serious adverse effects of therapy. (2C)
Indication for kidney biopsy A kidney biopsy for children aged ≥ 12 years is recommended because of the frequency of diagnoses other than minimal-change disease.
(LoE: Not applicable, GoR: Opinion-based)
• At the onset of nephrotic syndrome in patients: (Not Graded):
1. Whose age is < 1 year
2. With persistent hematuria and frank hematuria
3. Hypertension and renal dysfunction
4. Hypocomplementemia
5. Extrarenal symptoms (e.g., rash, purpura), since these patients are likely to have other histological types than minimal-change disease.
• In patients showing steroid resistance
• In patients given long-term calcineurin inhibitor therapy, even without renal dysfunction (at 2–3 years into the therapy)
Indications for kidney biopsy in children with SSNS are (Not Graded):
▪ Late failure to respond following initial response to corticosteroids
▪ A high index of suspicion for a different underlying pathology
▪ Decreasing kidney function in children receiving CNIs
Vaccination in children with SSNS Immunize with the 23-valent and heptavalent conjugated pneumococcal vaccines.
Immunize the immunosuppressed or actively nephrotic patient and household contacts with inactivated influenza vaccine yearly.
Defer immunization with live vaccines:
- Until prednisone dose is < 2 mg/kg/day (maximum: 20 mg).
- For 3 months from completion of therapy with cytotoxic agents or for 1 month from completion of other daily immunosuppression.
Provide varicella immunization if nonimmune based on immunization history, disease history, or serologic evaluation.
Provide postexposure immunoglobulin for nonimmune immunocompromised patients.
Consider intravenous acyclovir for immunosuppressed children at the onset of chicken pox lesions.
(LoE: Not applicable, GoR: Opinion-based)
• Perform immunizations, when applicable.
• Not use live attenuated vaccines in patients during steroid or immunosuppressant treatment.
• Attenuated vaccines may be determined on a case-by-case basis and according to the condition of the patient and epidemic (Grade B)
• Proactive vaccination to the family member of the patient if there is no history or vaccination against the prevalent infection prophylaxis with antiviral drugs (acyclovir or valaciclovir) in cases where the household has been in close contact with varicella
To reduce the risk of serious infections in children with SSNS (Not Graded):
▪ Provide pneumococcal vaccination to the children.
▪ Provide influenza vaccination annually to the children and their household contacts.
▪ Defer vaccination with live vaccines until prednisone dose is below either 1 mg/kg daily (< 20 mg/day) or 2 mg/kg on alternate days (< 40 mg on alternate days).
▪ Live vaccines are contraindicated in children receiving corticosteroid-sparing immunosuppressive agents.
▪ 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, urinary, or respiratory secretions of vaccinated contacts for 3–6 weeks after vaccination.
▪ Following close contact with varicella infection, administer varicella zoster immune globulin, if available, to nonimmune children on immunosuppressive agents
Relevant implementation tool(s) provided in the CPG Table 1. Monitoring recommendations for children with nephrotic syndrome • Fig. 1. Flowchart for the determination of treatment plan [27]
• Table 5. Examination findings of primary nephrotic syndrome [26]
• Fig. 1. Treatment of MCNS [26]
• Table 1. Diuretic agents available for infants/children [28]
• Table 2. 2Dietary reference intake for Japanese population [28]
• Table 3. Health classification by the status of nephrotic syndrome [28]
Translations into four languages: Japanese, German, Russian, and Turkish. The Canadian Society of Nephrology published a Commentary in 2014 on the KDIGO 2012 CPG (management of nephrotic syndrome in children) including the relevancy and applicability of the recommendations to the Canadian context.
  1. AAP American Academy of Pediatrics; CPGs clinical practice guidelines; CNI calcineurin inhibitor; CPG ID short identity or acronym; GoR grade of recommendation; JSPN Japanese Society of Paediatric Nephrology; KDIGO Kidney Disease: Improving Global Outcomes; LoE Level (or quality) of evidence; FRNS Frequently relapsing nephrotic syndrome, SSNS steroid-sensitive nephrotic syndrome; AAP 2009 CPG management of childhood onset nephrotic syndrome; JPNS 2014 CPG evidence-based clinical practice guidelines for nephrotic syndrome; KDIGO 2012 CPG clinical practice guideline for glomerulonephritis—Chapter 3; ISKDC International Study of Kidney Disease in Children; MCNS minimal change nephrotic syndrome; MMF mycophenolate mofetil