What is the recommended approach and treatment for nephrotic syndrome in children?

Nephrotic Syndrome in Children: Approach and Treatment

Initial treatment of new-onset nephrotic syndrome in children requires oral glucocorticoids (prednisone/prednisolone) for either 8 weeks (4 weeks daily followed by 4 weeks alternate-day) or 12 weeks (6 weeks daily followed by 6 weeks alternate-day), with the longer duration potentially reducing relapse risk. 1

Initial Diagnostic Approach

Before initiating treatment, assess for:

• Syndromic features (impaired growth, skeletal/neurodevelopmental/ocular abnormalities, deafness, genital ambiguity, facial dysmorphisms) which suggest genetic causes requiring different management 1
• Age considerations: Most cases in school-aged children represent minimal change disease, while very young children (<1 year) warrant earlier genetic testing 2, 3
• Baseline assessment: Proteinuria quantification, renal function, lipid profile, and infection/thrombosis risk 2

First-Line Treatment: Glucocorticoids

Dosing regimen:

• Initial phase: 60 mg/m²/day (or 2 mg/kg/day, maximum 60 mg) of oral prednisone/prednisolone daily for 4-6 weeks 1, 3
• Taper phase: 40 mg/m²/dose (or 1.5 mg/kg) on alternate days for 4-6 weeks 1, 3
• Total duration: Either 8 or 12 weeks total (1B recommendation) 1

The majority of children achieve complete remission with this approach, defining them as having steroid-sensitive nephrotic syndrome (SSNS) 2.

Management of Relapses

Prevention During Infections

Do NOT routinely give daily glucocorticoids during upper respiratory tract infections to prevent relapses in children with frequently relapsing or steroid-dependent nephrotic syndrome (1C recommendation) 1. The PREDNOS2 study demonstrated no benefit of this approach 1.

Exception: Consider 3 extra doses of low-dose prednisone (0.5 mg/kg/day) at infection onset only in children already on alternate-day prednisolone who have a history of repeated infection-associated relapses AND significant steroid-related morbidity 1.

Treatment of Subsequent Relapses

• Without glucocorticoid toxicity: Use the same glucocorticoid regimen as initial treatment 1
• With glucocorticoid toxicity: Consider shorter taper and/or more robust steroid-sparing approaches 1
• For prevention in frequently relapsing NS without toxicity: Low-dose, alternate-day oral prednisone/prednisolone may be used 1

Glucocorticoid-Sparing Agents

Indications for steroid-sparing therapy (1B recommendation): 1

• Children with frequently relapsing nephrotic syndrome who develop serious glucocorticoid-related adverse effects
• ALL children with steroid-dependent nephrotic syndrome

Agent Selection Based on Disease Pattern

For frequently relapsing nephrotic syndrome:

• Preferred agents: Oral cyclophosphamide or levamisole 1

For steroid-dependent nephrotic syndrome:

• Preferred agents: Mycophenolate mofetil, rituximab, calcineurin inhibitors (cyclosporin/tacrolimus), or to a lesser extent, oral cyclophosphamide 1

Important note: The 2025 KDIGO guideline eliminated the formal distinction between "first-line" and "alternative" agents, recognizing that agent selection should be tailored to the specific disease pattern 1.

Initiation Protocol

• Achieve remission with glucocorticoids before starting steroid-sparing agents 1
• Continue glucocorticoids for 2 weeks after initiating the steroid-sparing agent 1

Special Considerations for Rituximab

• Current trials report 1-4 doses, but insufficient data exist for specific dosing recommendations 1
• In complicated frequently relapsing or steroid-dependent cases, adding mycophenolate mofetil after rituximab can decrease treatment failure risk 1

Steroid-Resistant Nephrotic Syndrome (SRNS)

Definition: Failure to achieve complete remission after 4+ weeks of daily corticosteroid therapy 4

Initial second-line therapy (1C recommendation):

• Cyclosporin or tacrolimus as first choice 1, 4
• Calcineurin inhibitors may increase complete remission rates 3-4 fold compared to placebo/no treatment by 2-6 months 4
• Calcineurin inhibitors are superior to intravenous cyclophosphamide, increasing complete remission (RR 3.43) and complete/partial remission (RR 1.98) at 3-6 months 4

For calcineurin inhibitor-resistant SRNS:

• Rituximab may achieve remission in approximately 30% of children 1
• Evidence for mycophenolate mofetil remains very limited 1

Tacrolimus vs. Cyclosporin

• Similar efficacy for achieving remission 4
• Tacrolimus may reduce relapse rates during treatment (RR 0.22) 4
• Cyclosporin causes more hypertrichosis and gingival hyperplasia 4

Critical Monitoring and Complications

Acute complications requiring vigilance: 2

• Hypovolemia and acute kidney injury
• Infections (due to immunosuppression and urinary immunoglobulin loss)
• Thrombosis (from urinary antithrombin loss and hepatic procoagulant synthesis)
• Dyslipidemia

Long-term monitoring priorities:

• Minimize treatment-related side effects, particularly glucocorticoid toxicity 2
• Regular urine protein monitoring (though lack of insurance coverage for dipsticks in the US creates barriers) 5
• Disease characterization to guide treatment decisions 5

Genetic Considerations

Up to one-third of SRNS cases have a monogenic origin 2. Genetic testing should be considered, particularly in:

• Very young children (<1 year)
• Presence of syndromic features 1
• Initial steroid resistance
• Multidrug-resistant disease (which often progresses to kidney failure and can relapse post-transplant) 2

Prognosis

• Steroid-sensitive disease: Does not affect long-term renal function, but most children experience a relapsing course requiring repeated treatment with significant side effects 2
• Multidrug-resistant disease: Often leads to kidney failure and can recur after kidney transplantation 2
• A subset of patients maintain active disease into adulthood 2