What are the classifications of nephrotic syndrome based on steroid response and the recommended management for each category?

Classification and Management of Nephrotic Syndrome Based on Steroid Response

Nephrotic syndrome in children is classified by steroid response into steroid-sensitive (SSNS), frequently relapsing (FRNS), steroid-dependent (SDNS), and steroid-resistant (SRNS) categories, with management escalating from corticosteroids alone to glucocorticoid-sparing agents based on response pattern and toxicity. 1, 2

Classification Categories

Steroid-Sensitive Nephrotic Syndrome (SSNS)

• Children who achieve remission within 4 weeks of daily corticosteroid therapy are classified as steroid-sensitive, representing the majority of pediatric nephrotic syndrome cases 3
• These patients have excellent long-term kidney function prognosis, though 60-80% will experience relapses requiring additional treatment 4

Frequently Relapsing Nephrotic Syndrome (FRNS)

• Defined as children experiencing two or more relapses within 6 months of initial response, or four or more relapses within any 12-month period 2, 5
• This pattern indicates need for steroid-sparing strategies to minimize cumulative corticosteroid toxicity 6

Steroid-Dependent Nephrotic Syndrome (SDNS)

• Children who relapse during corticosteroid tapering or within 14 days of discontinuation are classified as steroid-dependent 2, 5
• All children with SDNS should receive glucocorticoid-sparing agents rather than continuing corticosteroids alone 6

Steroid-Resistant Nephrotic Syndrome (SRNS)

• Failure to achieve remission after 4 weeks or more of daily corticosteroid therapy defines steroid resistance 3, 7
• Up to one-third of SRNS cases have a monogenic origin requiring genetic evaluation 3
• SRNS carries significant risk of progression to kidney failure and requires second-line immunosuppression 8

Initial Treatment Approach

First Episode Management

• Start oral prednisone 60 mg/m²/day or 2 mg/kg/day (maximum 60 mg/day) as a single morning dose for 4-6 weeks, followed by alternate-day prednisone 40 mg/m² for 2-5 months 1
• Total treatment duration should be 8-12 weeks minimum, with longer initial courses up to 6 months reducing relapse risk 1
• Children under 1 year require specialized evaluation before initiating prednisolone, as they are significantly more likely to have genetic causes rather than idiopathic disease 9

Relapse Treatment

• For infrequent relapses, treat with prednisone 60 mg/m²/day until 3 consecutive days of remission, then switch to alternate-day prednisone 40 mg/m² for 4 weeks 1
• Daily glucocorticoids should not be routinely given during upper respiratory tract infections to reduce relapse risk in FRNS or SDNS patients 6

Glucocorticoid-Sparing Agent Selection

For Frequently Relapsing Nephrotic Syndrome Without Toxicity

• Low-dose, alternate-day oral prednisone/prednisolone can be used for relapse prevention 6
• When glucocorticoid-related adverse effects develop, oral cyclophosphamide (2 mg/kg/day for 8-12 weeks) or levamisole (2.5 mg/kg alternate days) are preferable first-line steroid-sparing agents 6, 1

For Steroid-Dependent Nephrotic Syndrome

• All children with SDNS require glucocorticoid-sparing agents rather than continuation with glucocorticoid treatment alone 6
• Mycophenolate mofetil, rituximab, calcineurin inhibitors (cyclosporin or tacrolimus), or cyclophosphamide are preferable options 6, 1
• The KDIGO Work Group no longer makes formal distinction between first-line and alternative agents, allowing flexibility based on individual patient factors 6

For Steroid-Resistant Nephrotic Syndrome

• Cyclosporin or tacrolimus should be used as initial second-line therapy for children with SRNS 6, 8
• Calcineurin inhibitors may increase complete or partial remission rates threefold compared to placebo or cyclophosphamide 7
• Rituximab may achieve remission in approximately 30% of children with calcineurin inhibitor-resistant SRNS 6
• In complicated FRNS or SDNS cases, mycophenolate mofetil after rituximab can decrease treatment failure risk 6

Key Management Principles

Timing of Glucocorticoid-Sparing Agents

• Patients should ideally be in remission with glucocorticoids prior to initiating glucocorticoid-sparing agents 6
• Continue glucocorticoids for 2 weeks following initiation of steroid-sparing agents 6

Monitoring for Toxicity

• In children with signs of glucocorticoid toxicity, shorter taper and more robust steroid-sparing approaches should be considered in subsequent relapses 6
• Close monitoring for complications including hypovolemia, acute kidney injury, infections, and thrombosis is warranted at onset and during relapses 3

Common Pitfalls

• Avoid treating children under 1 year with standard protocols without genetic evaluation, as they likely have congenital or genetic forms 9
• Do not continue corticosteroids alone in SDNS patients—this represents inadequate management per current guidelines 6
• Recognize that histological patterns (minimal change disease versus focal segmental glomerulosclerosis) do not correlate with treatment response, so management decisions should be based on steroid response pattern rather than biopsy findings 10