What is the best approach to manage steroid-sensitive nephrotic syndrome (SSNS) in a patient transitioning from childhood to adulthood, with a history of steroid responsiveness and potential long-term corticosteroid use?

Management of Steroid-Sensitive Nephrotic Syndrome Transitioning to Adulthood

For patients with childhood-onset steroid-sensitive nephrotic syndrome (SSNS) transitioning to adulthood, continue treating relapses with standard corticosteroid protocols and implement steroid-sparing agents for frequently relapsing or steroid-dependent disease, as approximately one-third of patients will have active disease persisting into adulthood. 1, 2

Understanding Disease Persistence into Adulthood

• 31% of patients with childhood-onset SSNS continue to have active disease in early adulthood, particularly those with steroid-dependent or frequently relapsing patterns during childhood 2
• Patients with steroid-dependent/frequently relapsing disease in childhood show significantly higher relapse rates from late childhood through adolescence (1.06 vs. 0.19 relapses/patient/year) compared to those who achieve sustained remission 2
• The traditional assumption that SSNS resolves by adulthood has been definitively challenged by longitudinal data 2

Treatment of Relapses in Transitioning Patients

For Infrequent Relapses

• Initiate prednisone 60 mg/m² or 2 mg/kg daily (maximum 60 mg/day) until achieving complete remission for at least 3 consecutive days 1
• After remission, switch to alternate-day prednisone 40 mg/m² or 1.5 mg/kg (maximum 40 mg on alternate days) for at least 4 weeks 1
• Recent evidence suggests lower doses (1-1.5 mg/kg/day) may achieve remission with significantly reduced cumulative steroid exposure, though response time may be slightly longer 3

For Frequently Relapsing or Steroid-Dependent Disease

• Treat relapses with daily prednisone until remission for 3 days, then alternate-day prednisone for at least 3 months 1
• Maintain remission with the lowest alternate-day prednisone dose that prevents relapses without major adverse effects 1
• If alternate-day therapy fails in steroid-dependent patients, use daily prednisone at the lowest effective dose 1
• During upper respiratory infections, increase from alternate-day to daily prednisone temporarily to prevent infection-triggered relapses 1

Steroid-Sparing Agents: Critical for Long-Term Management

Steroid-sparing agents are strongly recommended (Grade 1B) for patients with frequently relapsing or steroid-dependent SSNS who develop steroid-related adverse effects, which is particularly relevant for patients transitioning to adulthood with ongoing disease 1, 4

First-Line Steroid-Sparing Options

Calcineurin Inhibitors (CNIs)

• Cyclosporine 4-5 mg/kg/day in two divided doses is recommended as a corticosteroid-sparing agent (Grade 1C) 1
• Tacrolimus 0.1 mg/kg/day in two divided doses may be used instead when cosmetic side effects of cyclosporine (hirsutism, gingival hyperplasia) are unacceptable 1
• Monitor CNI levels regularly to limit nephrotoxicity and continue for at least 12 months, as most patients relapse when stopped 1
• For long-term remission maintenance, consider switching from CNI to mycophenolate mofetil to avoid cumulative nephrotoxicity 1

Cyclophosphamide

• Cyclophosphamide 2 mg/kg/day for 8-12 weeks (maximum cumulative dose 168 mg/kg) is recommended for frequently relapsing SSNS (Grade 1B) 1
• Do not start cyclophosphamide until remission is achieved with corticosteroids 1, 4
• Never give second courses of alkylating agents due to cumulative gonadal toxicity risk 1, 4
• Induces long-term remission in 25-70% of patients 5

Mycophenolate Mofetil (MMF)

• MMF 1200 mg/m²/day in two divided doses for at least 12 months is suggested as a steroid-sparing agent (Grade 2C) 1
• Most patients relapse when MMF is stopped, requiring prolonged therapy 1
• Target area under the curve >50 μg·h/mL for optimal efficacy 1

Rituximab

• Consider rituximab (375 mg/m² for 1-4 doses) only for steroid-dependent patients with continuing frequent relapses despite optimal combinations of prednisone and other steroid-sparing agents, or those with serious adverse effects 1, 4
• Recent data suggest rituximab has a pivotal role given evidence of B-cell involvement in SSNS pathogenesis 1

Agent Selection Strategy

• Choice depends on relapse pattern, steroid toxicity profile, monitoring capability, and patient preference 4
• No single agent demonstrates clear therapeutic superiority over others 4
• For cosmetically-conscious young adults, tacrolimus is preferable to cyclosporine 1
• Levamisole (2.5 mg/kg on alternate days for ≥12 months) is recommended (Grade 1B) but availability is limited in many countries 1

Monitoring and Adverse Effect Management

Steroid-Related Complications

• Long-term corticosteroid therapy causes hypertension, growth impairment, behavioral disturbances, osteopenia, and increased infection risk 6
• For patients anticipated to receive ≥5 mg prednisone equivalent for ≥3 months, initiate calcium and vitamin D supplementation, consider bisphosphonates, and encourage weight-bearing exercise 7
• Monitor bone mineral density in young adults, particularly females, as they are at increased osteoporosis risk 7

Agent-Specific Monitoring

• CNIs: Monitor serum creatinine regularly; perform kidney biopsy if function declines to distinguish CNI nephrotoxicity from disease progression 4, 8
• Cyclophosphamide: Weekly complete blood counts during treatment; monitor for hemorrhagic cystitis 1, 4
• Levamisole: Check CBC every 2-3 months, liver enzymes every 3-6 months, and ANCA titers every 6 months 1
• MMF: Monitor for gastrointestinal side effects; consider switching to enteric-coated formulations if intolerant 1

Critical Pitfalls to Avoid

• Do not abruptly discontinue corticosteroids due to risk of adrenal insufficiency, which may persist up to 12 months after prolonged therapy 7
• Do not taper steroids prematurely before steroid-sparing agents demonstrate efficacy 4
• Do not give alkylating agents during active relapse; always achieve remission with steroids first 1, 4
• Do not underestimate disease persistence; one-third of childhood-onset patients remain active into adulthood and require ongoing specialized care 2
• Do not continue CNIs indefinitely without monitoring; nephrotoxicity is cumulative and may be irreversible 4, 8

Transition Planning

• Educate patients on home urine dipstick monitoring for early relapse detection 4
• Establish care with adult nephrology before age 18 for patients with ongoing disease 2
• Patients with steroid-dependent or frequently relapsing patterns in late adolescence are at highest risk for adult disease activity and require close monitoring during transition 2
• Counsel regarding infection prevention, as upper respiratory infections commonly trigger relapses 1