Steroid-sensitive nephrotic syndrome in children

INTRODUCTION

A group of experts from the International Pediatric Nephrology Association (IPNA) has recently updated recommendations for steroid-resistant and steroid-sensitive nephrotic syndrome (SRNS and SSNS) in children [1, 2]. SSNS is now defined as idiopathic nephrotic syndrome [spot urinary protein:creatinine ratio (UPCR) ≥200 mg/mmol and albuminemia <30 g/l] responsive to 4 weeks of corticosteroid therapy with or without a confirmation period of 2 additional weeks (late SSNS). We present a summary of the new definitions and recommendations for diagnosis and management of SSNS in children (Fig. 1).

Important definitions

• Infrequently relapsing nephrotic syndrome: fewer than two relapses in the 6 months following remission of the initial episode or fewer than three relapses in any subsequent 12-month period.

• Frequently relapsing nephrotic syndrome (FRNS): two or more relapses in the first 6 months following remission of the initial episode or three or more relapses in any 12 months.

• Steroid-dependent nephrotic syndrome (SDNS): two or more consecutive relapses during recommended prednisone/prednisolone (PDN) therapy for the first presentation or relapse or within 14 days of its discontinuation.

• Sustained remission: no relapse over 12 months with or without therapy.

• SSNS controlled on therapy: infrequently relapsing NS or sustained remission while on immunosuppression in the absence of significant drug-related toxicity.

Indications for kidney biopsy

• Not indicated in the initial diagnostic workup of children with NS who present with typical features and age >1 year.

• Recommended in patients with atypical features including macroscopic haematuria, low C3 levels, acute kidney injury not related to hypovolemia, sustained hypertension, arthritis and/or rash.

• Considered in patients with infantile-onset NS (age 3–12 months), especially if genetic screening is not available.

• Considered in patients >12 years of age on a case-by-case basis.

• Recommended in patients diagnosed with SRNS (refer to Trautmann et al. [1]).

• Considered in patients with persistent microscopic haematuria in specific populations with a high incidence of glomerular diseases, such as immunoglobulin A nephropathy in East Asia.

Indications for genetic testing

• Not indicated in children with SSNS, including in familial forms.

• Recommended in patients with congenital and infantile NS and/or extrarenal features and/or a positive family history of SRNS.

• Recommended in patients diagnosed with SRNS.

TREATMENT

General measures

• Daily prednisone/prednisolone (PDN) for 4 weeks at 60 mg/m² or 2 mg/kg (maximum dose 60 mg/day) in a single morning dose.

• Evaluation after 4 weeks of treatment:

  • – No remission (SRNS): refer to specific recommendations for management of SRNS in children [1, 3].

  • – Complete remission (UPCR ≤20 mg/mmol; SSNS): decrease PDN to alternate days at 40 mg/m² or 1.5 mg/kg (maximum dose of 40 mg on alternate days) for 4 weeks.

  • – Partial remission (UPCR >20 but <200 mg/mmol (>0.2 but <2.0 mg/mg) and serum albumin ≥30 g/l): treat for an additional 2 weeks with oral PDN with or without three methylprednisolone pulses and/or renin-angiotensin system blockers (confirmation period) and re-evaluate at 6 weeks:

• No or partial remission at 6 weeks (SRNS): refer to specific recommendations for management of SRNS in children [1, 3].

• Complete remission at 6 weeks (late-responder SSNS): decrease PDN to alternate days at 40 mg/m² or 1.5 mg/kg (maximum dose of 40 mg on alternate days) for 4 weeks.

There is no randomized controlled trial comparing a 4 + 4 to a 6 + 6-week course of treatment for the initial episode of SSNS. Therefore, both are recommended in line with Kidney Disease: Improving Global Outcomes guidelines [2, 4, 5].

Treatment of relapses

• Single daily dose of PDN (2 mg/kg or 60 mg/m², maximum 60 mg) until complete remission [UPCR ≤20 mg/mmol (0.2 mg/mg) or negative or trace dipstick on ≥3 consecutive days].

• Then decrease to alternate day PDN (1.5 mg/kg/dose or 40 mg/m²/dose, maximum 40 mg) for 4 weeks.

• No tapering schedule during alternate day dosing.

Maintenance therapy

Introduction of a steroid-sparing agent is recommended in all children with SSNS not controlled on therapy, a complicated relapse, SDNS or FRNS (low-dose maintenance PDN given as an alternate-day or a daily dose can be attempted in FRNS).

Currently, due to the paucity of randomized controlled trials conducting head-to-head comparisons, there is little evidence to guide the choice of steroid-sparing immunosuppressive agents [6]. The decision should be made based on individual preference after a careful discussion with the patient and his/her parents, illustrating the pros and cons of each option and considering local rules for reimbursement and availability. A detailed description of side effects and an explanation of required monitoring is crucial.

Available steroid-sparing agents sorted by side-effect profile:

• Levamisole (LEV) [7]: 2–2.5 mg/kg on alternate days (maximum 150 mg). The main side effects (transient) include leucopenia, elevated transaminases, anti-neutrophil cytoplasmic antibody vasculitis (mostly if use is prolonged >2 years).

• Mycophenolate mofetil (MMF)/mycophenolic sodium (MPS) [8]: e.g. MMF 600 mg/m²/12 h (maximum 1500 mg/dose) targeting an area under the concentration–time curve from 0 to 12 h >50 mg × h/l. The main side effects (transient) include abdominal pain, diarrhoea, weight loss, leucopenia, anaemia and elevated transaminases.

• Calcineurin inhibitors (CNIs) [9]: e.g. tacrolimus 0.05–0.1 mg/kg/12 h (maximum 10 mg/dose) targeting trough levels of 3–7 ng/ml then using the lowest effective dose to maintain patients controlled on therapy, and avoiding prolonged use of CNIs. The main side effects include nephrotoxicity, hypertension, posterior reversible encephalopathy syndrome, new-onset diabetes mellitus (tacrolimus) and hirsutism (cyclosporin). If CNIs have to be continued >2–3 years, a kidney biopsy is recommended to exclude toxicity.

• Oral cyclophosphamide (CYC) [10]: single course of 8–12 weeks at 2 mg/kg/day (maximum 150 mg) and a cumulative dose <168 mg/kg. The main side effects include leukopenia, thrombocytopenia alopecia, haemorrhagic cystitis, infections, cancer and infertility.

• Anti-CD20 monoclonal antibodies (rituximab) [11, 12]: indicated in children >7–9 years of age with FRNS or SDNS who are not controlled on therapy after a course of treatment with at least one other steroid-sparing agent at an adequate dose, especially in case of non-adherence. Use one to four infusions of rituximab 375 mg/m² (maximum 1000 mg/dose). The main side effects include infusion reactions, prolonged hypogammaglobulinemia, neutropenia and severe infection.

Tapering and discontinuation of maintenance treatment should be considered in all children in sustained remission for at least 12 months.

FUNDING

None declared.

AUTHORS’ CONTRIBUTIONS

O.B. and A.T. contributed equally and should therefore serve as co-first authors. D.H. and M.V. contributed equally as well and should serve as co-last authors.

CONFLICT OF INTEREST STATEMENT

None declared.

REFERENCES