What is the treatment for minimal change disease?

Minimal Change Disease: Comprehensive Overview and Treatment

Clinical Background and Epidemiology

Minimal change disease (MCD) is the most common cause of idiopathic nephrotic syndrome in children (>75% of pediatric cases, 90% in children under 5 years) and accounts for approximately 20% of adult nephrotic syndrome cases. 1

• The hallmark presentation is nephrotic syndrome with massive proteinuria, edema, hypoalbuminemia, and hyperlipidemia 1
• The disease characteristically shows spontaneous remissions and relapses 1
• The risk of end-stage renal disease (ESRD) is extremely low, except in rare cases of severe acute tubular necrosis in elderly patients or those with pre-existing severe hypertension 1
• Long-term kidney survival is excellent in patients who respond to glucocorticoids 1

First-Line Treatment: Corticosteroids

Initial Treatment in Adults

High-dose oral glucocorticoids constitute first-line treatment for MCD in adults (Grade 1C), with prednisone 1 mg/kg/day (maximum 80 mg) given as a single daily dose. 1, 2

• The initial high dose should be maintained for a minimum of 4 weeks if complete remission is achieved 1, 2
• If complete remission is not achieved, continue high-dose treatment for a maximum of 16 weeks 1, 2
• Adults typically achieve remission rates of 50-60% with 8-week courses, but extending treatment duration to >16 weeks increases remission rates to approximately 80% 1
• After achieving remission, taper prednisone slowly over a total period of up to 6 months 2
• Tapering should begin 2 weeks after achieving remission 1

Initial Treatment in Children

Children should receive prednisone 60 mg/m²/day (or 2 mg/kg/day, maximum 60 mg) for 4-6 weeks, followed by 40 mg/m² on alternate days for 4-6 weeks. 1, 3

• Approximately 95% of children achieve complete remission within 4-8 weeks 1
• Increasing corticosteroid duration to 12 weeks improves sustained remission rates 1

Treatment of Relapses

For infrequent relapses (≤2 episodes within 6 months), use the same initial dose and duration of corticosteroids as for the first episode. 1, 2

• For frequent relapses in children, give daily prednisone until remission (at least 3 days), followed by alternate-day prednisone for at least 3 months 2

Steroid Toxicity Concerns

Prolonged glucocorticoid therapy carries significant risks including glucose intolerance, cushingoid features, infections, and hip osteonecrosis (particularly in elderly patients and post-menopausal women). 1

• More than half of steroid-responsive patients experience relapses 1
• Patients with frequent relapses (≥2 episodes within 6 months) have greater risk of becoming steroid-dependent 1

Second-Line Treatments for Frequently Relapsing/Steroid-Dependent Disease

When to Consider Alternative Therapies

Alternative immunosuppressive agents should be employed for frequently relapsing (≥2 relapses within 6 months) or steroid-dependent MCD, or when patients have contraindications/intolerance to high-dose corticosteroids (Grade 1C). 1

Calcineurin Inhibitors (CNIs)

Cyclosporine and tacrolimus are effective steroid-sparing agents for MCD.

Cyclosporine Dosing and Monitoring:

• Start at 2-5 mg/kg/day in two divided doses 1
• Target 12-hour trough level: 60-150 ng/mL in children; 80-120 ng/mL in adults 1
• Gradually increase dose at 2-week intervals until remission or maximum 5 mg/kg/day 1
• Continue for at least 12 months in children, 1-2 years in adults after achieving remission 1
• Taper very slowly to minimum dose that maintains remission (target ≤2 mg/kg/day) 1
• May be preferable in patients at risk for diabetic complications 1

Tacrolimus Dosing and Monitoring:

• Start at 0.05-0.1 mg/kg/day in two divided doses 1, 4
• Target 12-hour trough level: 5-10 ng/mL, aiming for lowest levels to maintain remission 1
• May be preferred over cyclosporine when cosmetic side effects (hirsutism, gingival hyperplasia) are unacceptable 1
• A 2020 randomized controlled trial showed tacrolimus monotherapy achieved 68% complete remission at 8 weeks versus 84% with prednisolone (not statistically significant, P=0.32), with similar relapse rates 4

Critical CNI Considerations:

• Cyclosporine is a "critical-dose drug"—small changes in dose or plasma concentration may result in clinically significant changes in efficacy/toxicity 1
• Prescribing physicians must specify the exact brand to be dispensed due to significant variation in generic formulations 1
• Brand switching or mixing can alter bioavailability, potentially reducing efficacy or increasing toxicity 1
• Monitor for nephrotoxicity: perform repeat renal biopsy every 2-3 years during long-term therapy 1
• Consider biopsy if serum creatinine increases >30% above baseline or maintenance dose required is >3.5 mg/kg/day 1
• If non-responsive after 6 months, discontinue CNI and perform repeat renal biopsy 1

Cyclophosphamide

In adults with multiple relapses, cyclophosphamide should be tried (12-week course) before initiating cyclosporine. 1

• Children: 2.0-2.5 mg/kg/day for 8-12 weeks 1
• Adults: Complete remission reported in 81% of cases, partial remission in additional 8% 1
• Wait until leukocyte counts return to normal before switching to cyclosporine to avoid combined immunosuppression risks 1
• Children with frequently relapsing nephrotic syndrome achieve longer remissions with cytotoxic agents than those with steroid dependency 1

Rituximab

Rituximab is an emerging option for frequently relapsing/steroid-dependent MCD (Grade 1C). 1

• A 2021 retrospective study showed median time to relapse of 66 months with rituximab versus 28 months with non-rituximab second-line therapies (P=0.170) 5
• Patients treated with rituximab may be less likely to require therapy changes and more likely to discontinue immunosuppression 5
• Currently under investigation in clinical trials as a steroid-sparing agent 6

Mycophenolate Mofetil (MMF) / Mycophenolic Acid Analogs (MPAA)

MMF or MPAA should be employed for frequently relapsing/glucocorticoid-dependent MCD (Grade 1C). 1

• Effective alternative for steroid-sparing therapy 1
• A 2013 study compared MMF versus cyclosporine in children with frequently relapsing nephrotic syndrome 1

Chlorambucil

Chlorambucil 0.2 mg/kg for 8 weeks is usually well tolerated in children. 1

Special Clinical Scenarios

Contraindications to Corticosteroids

For patients with contraindications or intolerance to high-dose corticosteroids (uncontrolled diabetes, psychiatric conditions, severe osteoporosis), use oral cyclophosphamide or CNIs. 1, 2

• Pregnancy represents a rare but important scenario where cyclosporine may be preferred, as high-dose corticosteroids are hazardous to mother and fetus, while cyclosporine is less harmful 1

Acute Kidney Injury

Acute kidney injury in newly diagnosed MCD should be treated with renal replacement therapy as indicated, along with corticosteroids as for first episode. 2

Steroid-Resistant MCD

If patients remain non-responsive to corticosteroids after 16 weeks, perform repeat renal biopsy to confirm diagnosis. 1

• Consider alternative diagnoses, particularly focal segmental glomerulosclerosis (FSGS) 1
• Unresolved MCD is considered the initial step in the pathological pathway leading to FSGS 6

Supportive Care and Monitoring

What NOT to Use Initially

For the initial episode of nephrotic syndrome associated with MCD, statins should NOT be used to treat hyperlipidemia, and ACE inhibitors or ARBs should NOT be used in normotensive patients to lower proteinuria (Grade 2D). 1, 2

Monitoring During Treatment

• Monitor for steroid-related side effects throughout treatment and tapering 2
• Check CNI levels regularly to verify adherence and avoid toxicity 1
• Perform repeat renal biopsy every 2-3 years during long-term CNI therapy 1
• Monitor for complications including dyslipidemia, infection, and thrombosis 3

Relapse Management Strategy

• If symptoms recur during tapering, return to pre-relapse dose and decrease more gradually (within 4-8 weeks) to the dose at which relapse occurred 2
• A 2018 retrospective study found no significant difference in outcomes between high-dose (>20 mg/day) versus low-dose (10-20 mg/day) prednisolone for relapse treatment in adults 7

Treatment Algorithm Summary

Adults:

1. Initial episode: High-dose prednisone 1 mg/kg/day (max 80 mg) for 4-16 weeks 1, 2
2. Infrequent relapses: Repeat initial corticosteroid regimen 1, 2
3. Frequent relapses/steroid-dependent: Try cyclophosphamide 12 weeks first 1
4. If cyclophosphamide fails or not durable: Cyclosporine, tacrolimus, rituximab, or MMF 1
5. Steroid contraindications: Proceed directly to cyclophosphamide or CNIs 1, 2

Children:

1. Initial episode: Prednisone 60 mg/m²/day for 4-6 weeks, then alternate-day for 4-6 weeks 1, 3
2. Frequent relapses: Cyclophosphamide 8-12 weeks or CNIs 1
3. Steroid-dependent: CNIs (cyclosporine or tacrolimus) for ≥12 months 1
4. Alternative options: MMF, rituximab, or chlorambucil 1

Common Pitfalls to Avoid

• Avoid prolonged high-dose corticosteroid therapy without considering steroid-sparing agents in patients with frequent relapses or steroid dependence 1
• Never switch CNI brands without careful reassessment of blood concentrations 1
• Do not stop CNIs abruptly—most patients relapse upon discontinuation 1
• Avoid premature discontinuation of therapy—CNIs should continue for at least 12 months in children, 1-2 years in adults 1
• Do not overlook nephrotoxicity monitoring during long-term CNI therapy 1

Prognosis

• The course of nephrotic syndrome in most patients is characterized by relapse and remission 3
• During median follow-up of 81 months in one study, no patients developed ESRD 5
• Long-term kidney survival is excellent in glucocorticoid-responsive patients 1