Nephrotic Syndrome in Children: A Comprehensive Scientific Review of Pathophysiology, Genetics, and Clinical Management

Infantile NS: Onset between 3-12 months of age. Approximately 50% of cases are genetic in origin.

Childhood NS: Onset after 12 months of age. This represents the most common presentation, with minimal change disease (MCD) accounting for >90% of cases in children aged 1-10 years.

2.3 Response-Based Classification (Complete with All Types and Subtypes)

The response to initial glucocorticoid therapy serves as the most clinically relevant classification system, determining prognosis, guiding management decisions, and predicting long-term outcomes.

2.3.1 Steroid-Sensitive Nephrotic Syndrome (SSNS)

Definition: Achievement of complete remission within four weeks of daily prednisone therapy at 60 mg/m²/day (maximum 60 mg/day).

Key Features:

• Represents approximately 80-90% of childhood NS cases

• Associated with minimal change disease (MCD) in >90% of cases

• Excellent long-term prognosis with normal kidney function

• May experience relapses (approximately 70-80% of patients)

Subtypes Based on Clinical Course:

A. Infrequent Relapsing NS (IRNS)

Definition: Less than two relapses within the first six months following initial remission, or less than three relapses in any 12-month period.

Clinical Course:

• Affects approximately 10-20% of SSNS patients

• Responds well to short glucocorticoid courses

• May achieve prolonged remission or resolution with age

• Typically does not require steroid-sparing agents

Management: Prednisone 60 mg/m²/day (maximum 60 mg/day) until remission (typically 1-2 weeks), followed by alternate-day therapy 40 mg/m² every other day for 2-4 weeks, then discontinue.

B. Frequently Relapsing NS (FRNS)

Definition: Two or more relapses within six months of initial remission, or three or more relapses in any 12-month period.

Clinical Course:

• Affects approximately 25-30% of SSNS patients

• Increased risk of cumulative steroid toxicity (growth impairment, obesity, osteoporosis)

• Requires steroid-sparing agents to minimize steroid exposure

Subtypes of FRNS:

i. FRNS Triggered by Viral Infections:

• Relapses occur during or immediately following viral upper respiratory infections

• May benefit from short "pre-emptive" steroid courses

• Regimen: Prednisone 40 mg/m²/day for 5-7 days at onset of viral symptoms

• If frequent relapses continue, initiate steroid-sparing therapy

ii. FRNS Requiring Maintenance Steroids:

• Relapses occur even when child is on maintenance therapy

• Requires steroid-sparing agents such as levamisole or MMF

• May eventually progress to steroid dependence

Management:

• First-line (where available): Levamisole 2-2.5 mg/kg on alternate days (maximum 150 mg/dose)

• First-line (USA/Canada): Mycophenolate mofetil (MMF) 600 mg/m²/dose twice daily (maximum 2 g/day)

• Second-line: Calcineurin inhibitors (tacrolimus or cyclosporine)

• Third-line: Rituximab (consider for children ≥7 years)

C. Steroid-Dependent NS (SDNS)

Definition: Two consecutive relapses occurring during glucocorticoid tapering or within 14 days of treatment discontinuation.

Clinical Course:

• Represents a more severe form of FRNS

• High cumulative steroid exposure

• Requires steroid-sparing agents to discontinue steroids

• May have a protracted clinical course lasting into adulthood

Subtypes of SDNS:

i. Early Steroid Dependence:

• Onset of dependence within first year of diagnosis

• More likely to require long-term steroid-sparing agents

• Higher risk of steroid-related complications

ii. Late Steroid Dependence:

• Develops after years of infrequent relapses

• May indicate changing disease biology

• Still responds to steroid-sparing agents

Management:

• First-line: Levamisole 2-2.5 mg/kg on alternate days (where available)

• Alternative: MMF 600 mg/m²/dose BID

• CNI therapy: Tacrolimus 0.10-0.20 mg/kg/day BID, target trough 4-8 ng/mL OR Cyclosporine 3-5 mg/kg/day BID, target trough 80-120 ng/mL

• Rituximab: 375 mg/m²/dose (1-4 doses) for children ≥7 years failing other therapies

2.3.2 Steroid-Resistant NS (SRNS)

Definition: Persistent proteinuria (UPCR ≥20 mg/mmol or >trace on urine dipstick) after four weeks of daily prednisone therapy at 60 mg/m²/day, followed by a two-week confirmation period.

Key Features:

• Represents approximately 10-20% of childhood NS cases

• Associated with poor long-term prognosis

• Approximately one-third have monogenic etiology

• High risk of progression to end-stage kidney disease

• Requires aggressive diagnostic evaluation and specialized management

Subtypes Based on Timing of Onset:

A. Primary (Congenital/Infantile) SRNS

Definition: Steroid resistance presenting in the first year of life.

Clinical Course:

• Almost always monogenic

• NPHS1 variants (congenital NS, Finnish type) - onset <3 months

• NPHS2 variants - onset typically >3 months

• WT1 variants - associated with Denys-Drash syndrome

• LAMB2 variants - Pierson syndrome

• PLCE1 variants - diffuse mesangial sclerosis

Management:

• Genetic testing is diagnostic

• Supportive management (albumin infusions, nutritional support)

• Avoid immunosuppression (ineffective)

• Consider bilateral nephrectomy for severe complications, followed by transplantation

B. Childhood-Onset SRNS

Definition: Steroid resistance presenting after 12 months of age.

Clinical Course:

• More likely to be non-genetic (approximately 60-70%)

• Associated with FSGS histology in many cases

• May respond to calcineurin inhibitors in 70-80% of non-genetic cases

• Progressive course with high risk of ESKD

Subtypes of Childhood-Onset SRNS:

i. Primary SRNS (No Identified Etiology):

• Likely immune-mediated or due to circulating permeability factors

• Best chance of response to immunosuppressive therapy

• Good prognosis if remission achieved

• Management: Calcineurin inhibitors (tacrolimus or cyclosporine) + RAAS inhibitors

ii. Monogenic SRNS (Identified Gene Variant):

• Poor response to immunosuppression

• Specific gene determines extrarenal manifestations

• Prognosis variable by gene:

  • NPHS2: Mean age of ESKD 6.6 years

  • WT1: Rapid progression, requires Wilms tumor surveillance

  • COQ2/COQ6/PDSS2/COQ8B: May respond to CoQ10 supplementation

  • ACTN4: Autosomal dominant, slower progression

iii. Secondary SRNS:

• Due to identifiable cause (infection, autoimmune disease)

• Treat underlying condition

• Immunosuppression directed at primary disease (e.g., lupus nephritis)

Management:

• Genetic testing is diagnostic

• Kidney biopsy recommended (unless genetic testing provides diagnosis)

• Immunosuppressive therapy: Calcineurin inhibitors (tacrolimus or cyclosporine)

• RAAS inhibition: ACEI or ARB for proteinuria reduction and renoprotection

• Alternative therapies: MMF, rituximab (reserved for CNI failure)

C. Late Steroid Resistance

Definition: Development of steroid resistance after an initial period of steroid responsiveness (i.e., patient had SSNS but subsequently becomes steroid-resistant).

Clinical Course:

• Occurs in <5% of SSNS patients

• May indicate transition to FSGS or other histologic lesion

• Worse prognosis than maintaining steroid sensitivity

• Requires re-evaluation and intensified therapy

Management:

• Re-evaluation: Kidney biopsy, genetic testing

• Immunosuppression: Calcineurin inhibitors (rather than levamisole or MMF)

• Tacrolimus: 0.10-0.20 mg/kg/day BID, target trough 4-8 ng/mL

• Cyclosporine: 3-5 mg/kg/day BID, target trough 80-120 ng/mL

• Response less predictable than primary SRNS

2.3.3 Slow Responders

Definition: Patients in whom proteinuria resolves only after the confirmation period (i.e., after receiving additional 2 weeks of steroids or intravenous methylprednisolone).

Clinical Course:

• May have a slightly worse long-term prognosis than those who achieve rapid remission

• Still considered SSNS (delayed response)

• Relapse rates similar to SSNS

Management:

• Confirmation period: Continue oral prednisone for additional 2 weeks OR add IV methylprednisolone 1000 mg/1.73m² every other day for 3 doses

• Once remission achieved: Continue with standard SSNS follow-up

• Consider steroid-sparing agents if frequent relapses develop

2.3.4 Summary Classification Table

IS: immunosuppression; CNI: calcineurin inhibitor; RAAS: renin-angiotensin-aldosterone system