What is the recommended treatment for minimal‑change disease presenting as nephrotic syndrome?

Treatment of Minimal Change Disease with Nephrotic Syndrome

High-dose oral glucocorticoids constitute the initial treatment for minimal change disease presenting as nephrotic syndrome, with prednisone 1 mg/kg/day (maximum 80 mg) or 2 mg/kg on alternate days (maximum 120 mg) for a minimum of 4 weeks and up to 16 weeks, followed by a slow taper over 6 months. 1

Initial Treatment Approach

First-Line Corticosteroid Therapy

Adults require biopsy confirmation before treatment, unlike children. 1 The standard regimen is:

• Prednisone 1 mg/kg/day (maximum 80 mg) as a single daily dose, OR
• 2 mg/kg on alternate days (maximum 120 mg) 1, 2
• Continue high-dose therapy for minimum 4 weeks, maximum 16 weeks until complete remission 1, 2
• Begin tapering 2 weeks after achieving complete remission 1, 2
• Total treatment course (high-dose plus taper) should last 6 months 2

Adults require significantly longer treatment duration (12-16 weeks) compared to children (4-6 weeks) to achieve remission. 1, 3 Response typically occurs within 4-8 weeks in adults, though it may take the full 16 weeks. 2

Tapering Protocol

• Reduce prednisone by 5 mg every 1-2 weeks after achieving remission 2
• The entire treatment course should span 6 months total to minimize relapse risk 2
• Do not stop steroids before 4 weeks even if remission occurs earlier, as premature cessation increases relapse risk 2

Alternative First-Line Therapy

Calcineurin inhibitors (CNIs) should be considered as first-line therapy instead of corticosteroids in patients with:

• Uncontrolled diabetes mellitus
• Severe psychiatric conditions
• Severe osteoporosis
• Morbid obesity 1, 2, 4

CNI dosing:

• Cyclosporine: 3-5 mg/kg/day in two divided doses, targeting trough levels of 100-175 ng/mL 1, 2
• Tacrolimus: 0.05-0.1 mg/kg/day in two divided doses, targeting trough levels of 5-10 ng/mL 1, 2
• When using CNIs, add low-dose prednisone (≈0.15 mg/kg/day) 2
• Continue CNI therapy for at least 4-6 months before declaring treatment failure 2

Management of Relapses

Infrequent Relapses

Treat with the same corticosteroid regimen that induced initial remission:

• Prednisone 1 mg/kg/day (maximum 80 mg) until remission (minimum 3 consecutive days proteinuria-free) 5
• Then switch to 40 mg/m² on alternate days for at least 4 weeks 1, 5

Relapses are extremely common, occurring in 34-85% of adults and up to 71% of children. 5, 3 Most relapses occur within the first 6-12 months after achieving remission. 3

Frequent Relapses or Steroid Dependence

Avoid repeated high-dose steroid courses due to cumulative toxicity. 2 Instead, transition to steroid-sparing agents:

First-line steroid-sparing options (in order of preference based on evidence):

1. Cyclophosphamide: 2-2.5 mg/kg/day for 8-12 weeks 1, 5

   • Achieves complete remission in 51% and partial remission in additional 23% 1
   • Induces longer remissions in frequently relapsing patients 5
   • Major limitation: cumulative gonadal toxicity; keep total dose below 200 mg/kg to minimize infertility risk 6

2. Rituximab: 375 mg/m² weekly for 4 doses 1

   • Increasingly preferred due to favorable safety profile
   • Check hepatitis B surface antigen and QuantiFERON before administration 1

3. Calcineurin inhibitors (cyclosporine or tacrolimus) 1, 5

   • Achieve complete remission in 73-82% of steroid-dependent adults 5, 6
   • Should be continued for at least 12 months, then tapered to minimum effective dose 1
   • Critical monitoring: Check serum creatinine regularly; discontinue if creatinine rises >30% above baseline and doesn't plateau after dose reduction 1, 5
   • Consider repeat renal biopsy at 12-24 months to assess for CNI nephrotoxicity, especially if creatinine elevated or maintenance dose >3.5 mg/kg/day 5

4. Mycophenolate mofetil 1

   • Reserved for patients intolerant of corticosteroids, cyclophosphamide, and CNIs 5
   • Lower quality evidence compared to other agents 5

Steroid Resistance

Steroid resistance is defined as no remission after 8-16 weeks of adequate corticosteroid therapy. 2, 4

Management approach:

• Switch to CNI-based regimen rather than continuing high-dose steroids beyond 16 weeks 1, 2
• Consider repeat renal biopsy to verify diagnosis and exclude focal segmental glomerulosclerosis 1, 5
• Cyclosporine achieves complete remission in 67% of steroid-resistant children and 61% of adults 6

Supportive Care During Active Nephrotic Syndrome

• Loop diuretics (furosemide) as first-line for severe edema 4
• Dietary sodium restriction to <2.0 g/day 4
• Avoid routine IV albumin infusions; use only if clinical indicators of hypovolemia present (hypotension, tachycardia, poor perfusion) 4
• Pneumococcal and annual influenza vaccination before or early in immunosuppressive therapy 4

Monitoring and Follow-Up

During Active Treatment

• Monitor urine protein daily using dipstick or spot urine protein-to-creatinine ratio 4
• Complete remission defined as: urine protein <200 mg/g (<20 mg/mmol) or trace/negative dipstick for 3 consecutive days 2, 4
• Check serum creatinine, estimated GFR, and serum potassium within 2-4 weeks of initiating therapy 2

Post-Remission Surveillance

• Every 3-6 months for patients in sustained remission to detect early relapse 5
• Measure serum creatinine and estimated GFR at each visit 5
• Check blood pressure at every visit 5

Long-Term Prognosis

Long-term kidney survival is excellent in MCD patients who respond to glucocorticoids, with fewer than 5% progressing to end-stage renal disease and 15-year patient survival of 83-98%. 1, 5, 3 However, prognosis is less certain for patients who do not respond to initial therapy. 1

Critical Pitfalls to Avoid

• Do not exceed 16 weeks of high-dose steroids without response; toxicity outweighs benefit 1, 2
• Do not exceed 80 mg/day (or 120 mg on alternate days); higher doses do not improve response but markedly increase toxicity 2
• Do not declare steroid resistance until at least 8 weeks of adequate therapy completed 4
• Do not stop therapy prematurely if partial response is occurring; continue up to 16 weeks 4
• Do not use statins solely to treat hyperlipidemia or ACE inhibitors/ARBs solely to lower proteinuria in normotensive patients during remission 5