What are the typical and atypical forms of nephrotic syndrome in children and how should each be managed?

Typical vs Atypical Nephrotic Syndrome in Children

Typical nephrotic syndrome in children presents before age 12 without syndromic features or family history and should be treated empirically with oral glucocorticoids for 8-12 weeks without kidney biopsy, while atypical presentations (age >12 years, syndromic features, family history, gross hematuria, hypertension, renal impairment, or hypocomplementemia) require kidney biopsy and/or genetic testing before treatment. 1

Defining Typical Presentation

Typical nephrotic syndrome has these characteristics:

• Age <12 years
• No syndromic features (normal growth, no skeletal/neurodevelopmental/ocular abnormalities, no deafness, no genital ambiguity, no facial dysmorphisms)
• No family history of kidney disease
• Absence of red flags: no gross hematuria, normal blood pressure, normal renal function, normal complement levels 1

Approximately 90% of these children respond to corticosteroids and have minimal change disease histologically 2, 3.

Defining Atypical Presentation

Atypical features that mandate biopsy and/or genetic testing include 1, 4:

• Age >12 years at onset
• Syndromic features (impaired growth, skeletal/neurodevelopmental/ocular abnormalities, deafness, genital ambiguity, facial dysmorphisms)
• Positive family history of nephrotic syndrome or kidney disease
• Gross hematuria (45% of atypical cases)
• Hypertension (50% of atypical cases)
• Renal impairment (19% of atypical cases)
• Hypocomplementemia (15% of atypical cases)

These atypical presentations are associated with non-minimal change histology in 90% of cases, most commonly mesangial proliferative glomerulonephritis (47.5%), and only 43% respond to steroids 4.

Management Algorithm for Typical Nephrotic Syndrome

Initial Treatment

Oral prednisone/prednisolone should be given for either 8 weeks (4 weeks daily + 4 weeks alternate-day) or 12 weeks (6 weeks daily + 6 weeks alternate-day). 1 Both regimens are equally effective at inducing remission.

Classification After Initial Treatment

Steroid-Sensitive Nephrotic Syndrome (SSNS):

• Achieves complete remission within 4-6 weeks of glucocorticoid therapy
• 70-80% will relapse at least once 5

Infrequent Relapsers:

• Treat each relapse with glucocorticoids using the same regimen 1

Frequent Relapsers (without glucocorticoid toxicity):

• Consider low-dose alternate-day oral prednisone/prednisolone for relapse prevention 1
• Do NOT routinely give daily glucocorticoids during upper respiratory infections - the PREDNOS2 study showed no benefit 1
• Exception: For children already on low-dose alternate-day prednisolone with repeated infection-associated relapses, consider 3 extra doses of low-dose (0.5 mg/kg/day) prednisolone at infection onset 1

Frequent Relapsers (with glucocorticoid toxicity) or Steroid-Dependent:

• Glucocorticoid-sparing agents are mandatory 1
• For frequently relapsing disease: cyclophosphamide or levamisole are preferable 1
• For steroid-dependent disease: mycophenolate mofetil, rituximab, calcineurin inhibitors (cyclosporine/tacrolimus), or cyclophosphamide are preferable 1
• Patients should be in remission before starting these agents, with glucocorticoids continued for 2 weeks after initiation 1
• For complicated cases: mycophenolate mofetil after rituximab decreases treatment failure risk 1

Steroid-Resistant Nephrotic Syndrome (SRNS):

• Cyclosporine or tacrolimus as initial second-line therapy 1
• For calcineurin inhibitor-resistant SRNS: rituximab achieves remission in approximately 30% of children 1
• Up to one-third have monogenic causes requiring genetic testing 2

Management Algorithm for Atypical Nephrotic Syndrome

Immediate Steps

1. Kidney biopsy and/or genetic testing 1
2. Referral to specialty center 1
3. Screen and treat infections before biopsy 4
4. Control hypertension before biopsy 4

Treatment Based on Biopsy Results

• Treatment depends on histological diagnosis (mesangial proliferative GN, focal segmental glomerulosclerosis, membranoproliferative GN, etc.)
• Calcineurin inhibitors for most steroid-resistant cases 1, 6
• Renin-angiotensin-aldosterone system blockade for proteinuria reduction 1

Critical Pitfalls to Avoid

Do not perform kidney biopsy in typical presentations - this exposes children to unnecessary procedural risk when 90% have minimal change disease and will respond to steroids 2, 3.

Do not give prophylactic steroids during infections in frequently relapsing/steroid-dependent patients - the 2025 KDIGO guidelines explicitly recommend against this based on PREDNOS2 trial data showing no benefit 1.

Do not delay glucocorticoid-sparing agents in steroid-dependent patients - continuing glucocorticoids alone causes significant morbidity including growth retardation, obesity, behavioral changes, and bone disease 1.

Do not miss genetic testing in atypical cases - monogenic causes account for up to one-third of steroid-resistant cases and fundamentally change prognosis and management 2.

Do not use the same treatment approach for all relapsing patients - the 2025 guidelines emphasize tailoring steroid-sparing agent selection based on whether the patient has frequently relapsing versus steroid-dependent disease 1.