What is the next step in treatment for pediatric patients with steroid-resistant nephrotic syndrome (SRNS) after failed steroid therapy?

Management of Steroid-Resistant Nephrotic Syndrome in Pediatrics

For pediatric patients with steroid-resistant nephrotic syndrome (SRNS), calcineurin inhibitors (CNIs) are recommended as the first-line therapy after failed steroid treatment, combined with ACE inhibitors or ARBs to reduce proteinuria. 1

Definition and Initial Evaluation

Steroid resistance is defined after a minimum of 8 weeks of corticosteroid treatment without achieving remission 1. Before initiating second-line therapy, the following evaluations are essential:

• Diagnostic kidney biopsy
• Assessment of kidney function (GFR or eGFR)
• Quantification of urine protein excretion 1

Treatment Algorithm

First-Line Therapy for SRNS

1. Calcineurin Inhibitors (Strong recommendation, 1B evidence)

   • Cyclosporine: 4-5 mg/kg/day in two divided doses 1
   • Tacrolimus: 0.1 mg/kg/day in two divided doses (preferred when cosmetic side effects of cyclosporine are unacceptable) 1
   • Duration:
     • Continue for minimum 6 months
     • If no partial/complete remission by 6 months, discontinue 1
     • If partial/complete remission achieved, continue for minimum 12 months 1
   • Always monitor CNI levels to limit toxicity 1

2. Adjunctive Therapy (to be used with CNIs)

   • Low-dose corticosteroids should be combined with CNI therapy 1
   • ACE inhibitors or ARBs (Strong recommendation, 1B evidence) 1

Second-Line Options for CNI Failure

If remission is not achieved with CNIs, consider:

1. Mycophenolate mofetil (MMF) (2D evidence)

   • Dosage: 1200 mg/m²/day in two divided doses 2
   • Duration: At least 12 months 1

2. High-dose corticosteroids (2D evidence) 1

3. Combination therapy with MMF and corticosteroids (2D evidence) 1

4. Rituximab - Consider only in cases with continuing frequent relapses despite optimal combinations of prednisone and corticosteroid-sparing agents 1

Important Caution

Cyclophosphamide should NOT be given to children with SRNS (2B evidence) 1

Management of Relapse After Complete Remission

If relapse occurs after achieving complete remission, restart therapy using one of:

1. Oral corticosteroids
2. Return to previously successful immunosuppressive agent
3. Alternative immunosuppressive agent to minimize cumulative toxicity 1

Monitoring and Supportive Care

1. Regular monitoring:

   • Proteinuria levels
   • Kidney function
   • Drug levels for CNIs
   • Blood pressure
   • Growth parameters 2

2. Infection prevention:

   • Pneumococcal vaccination
   • Annual influenza vaccination
   • Defer live vaccines until prednisone dose is <1 mg/kg/day or <2 mg/kg on alternate days
   • Live vaccines are contraindicated in children on immunosuppressive agents 1, 2

Clinical Considerations and Pitfalls

• Kidney biopsy timing: Essential before initiating second-line therapy to guide treatment decisions 1

• CNI toxicity: Monitor for decreasing kidney function in children receiving CNIs, which may indicate nephrotoxicity 1

• Genetic testing: Consider genetic testing in SRNS patients, as 11-30% may have a monogenic cause, which could influence treatment decisions 2

• Treatment duration: Inadequate duration of therapy is a common pitfall; CNIs should be continued for at least 12 months if partial remission is achieved 1, 2

• Medication side effects: Long-term corticosteroid therapy can lead to hypertension, short stature, behavioral disturbances, and osteopenia 3

The evidence strongly supports CNIs as the initial therapy for SRNS, with significantly better outcomes compared to cyclophosphamide. The 2025 KDIGO guidelines continue to recommend cyclosporine or tacrolimus as initial second-line therapy for children with SRNS (1C evidence) 1. This approach has been shown to achieve remission in a substantial proportion of patients, which is critical for preventing progression to end-stage renal disease 4.