What is Steroid-Resistant Nephrotic Syndrome (SRNS)?

Steroid-Resistant Nephrotic Syndrome (SRNS)

Steroid-resistant nephrotic syndrome (SRNS) is defined as persistent proteinuria despite treatment with corticosteroids for at least 8 weeks, representing a challenging subset of nephrotic syndrome with higher risk of progression to end-stage renal disease. 1

Diagnosis and Definition

SRNS is characterized by:

• Persistent proteinuria despite adequate steroid therapy
• Lack of remission after 8 weeks of corticosteroid treatment 1
• Associated with hypoalbuminemia, edema, and hyperlipidemia

The diagnosis requires:

• Confirmation of steroid resistance after minimum 8 weeks of treatment
• Kidney biopsy to determine histological subtype
• Evaluation of kidney function (GFR/eGFR)
• Quantification of urine protein excretion 1

Evaluation Process

1. Kidney Biopsy: Mandatory in all SRNS cases to determine histological pattern (most commonly focal segmental glomerulosclerosis) 1

2. Genetic Testing: Should be performed in all patients who develop SRNS before age 25, as approximately 30% have identifiable genetic mutations 2, 3

   • Particularly important in:
     • Early-onset cases (85% of cases with onset before 3 months)
     • Familial cases
     • Syndromic presentations 3

3. Laboratory Assessment:

   • Quantification of proteinuria (urine protein/creatinine ratio)
   • Serum albumin
   • Kidney function tests
   • Lipid profile 1

Treatment Algorithm

First-Line Treatment

Calcineurin inhibitors (CNIs) are the recommended first-line therapy for SRNS patients after confirming diagnosis. 1

• Cyclosporine: 3 mg/kg twice daily with target trough levels of 50-100 ng/ml 1, 4

  • Continue for minimum 6 months to assess response
  • If partial or complete remission achieved by 6 months, continue for at least 12 months
  • Maximum duration typically 24 months to minimize nephrotoxicity risk 1
  • Monthly monitoring of serum creatinine is essential

• Combined therapy: Low-dose corticosteroids should be given with CNI therapy 1

Second-Line Options (for CNI failure)

For patients who fail to achieve remission with CNIs:

1. Mycophenolate mofetil (MMF): 600 mg/m² per dose twice daily for 6-24 months 1

   • Monthly monitoring of white blood count required

2. High-dose corticosteroids: May be considered in selected cases 1

3. Combination therapy: MMF plus low-dose corticosteroids 1

Additional Treatments

• ACE inhibitors or ARBs: Recommended for all SRNS patients to reduce proteinuria 1

• Avoid cyclophosphamide: Not recommended for SRNS treatment 1

Management of Relapse After Remission

If relapse occurs after achieving complete remission:

• Restart oral corticosteroids, OR
• Return to previously successful immunosuppressive agent, OR
• Try alternative immunosuppressive agent to minimize cumulative toxicity 1

Special Considerations

Genetic Forms of SRNS

• Genetic testing is crucial as it may:

  • Provide definitive diagnosis
  • Identify treatable forms (e.g., coenzyme Q10 deficiency)
  • Help avoid unnecessary immunosuppression
  • Guide transplant decisions (lower recurrence risk) 2, 3

• Important genetic considerations:

  • Patients with mutations in coenzyme Q10 biosynthesis genes (COQ2, COQ6, ADCK4, PDSS2) may benefit from coenzyme Q10 supplementation
  • Patients with PLCE1 mutations may respond to steroids or cyclosporine
  • Patients with CUBN mutations may benefit from vitamin B12 3

Monitoring and Follow-up

• Regular assessment of kidney function
• Monitoring for CNI nephrotoxicity (consider kidney biopsy if decreasing function)
• Blood pressure monitoring
• Growth monitoring in children
• Surveillance for infections 1

Prognosis

• Non-genetic SRNS: ~30% risk of post-transplant recurrence 5
• Genetic SRNS: Negligible risk of post-transplant recurrence but higher risk of progression to ESRD 5
• Response to immunosuppression is a strong predictor of favorable long-term outcome 5

Common Pitfalls to Avoid

1. Delayed diagnosis: Failing to define steroid resistance after 8 weeks of therapy
2. Skipping kidney biopsy: Essential for diagnosis and treatment planning
3. Overlooking genetic testing: Critical in patients <25 years old
4. Continuing ineffective CNI therapy: Should be discontinued if no response after 6 months
5. Using cyclophosphamide: Not recommended for SRNS
6. Inadequate monitoring: Regular assessment of kidney function and drug levels is essential

By following this structured approach to diagnosis and management, outcomes for patients with SRNS can be optimized while minimizing treatment-related complications.