What is the treatment for minimal change disease?

Minimal Change Disease: Comprehensive Overview

Epidemiology and Clinical Background

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), while accounting for approximately 20% of adult cases. 1

• The major characteristic is nephrotic syndrome, which may be persistent or spontaneously remit and recur 1
• The risk of end-stage renal disease (ESRD) in MCD is extremely low, with exceptions being severe acute tubular necrosis in elderly patients and those with pre-existing severe hypertension 1
• Long-term kidney survival is excellent in MCD patients who respond to glucocorticoids 1

First-Line Treatment: Corticosteroids

Initial Treatment in Adults

High-dose oral glucocorticoids constitute first-line treatment for MCD, with prednisone 1 mg/kg/day (maximum 80 mg) given as a single daily dose for a minimum of 4 weeks if complete remission is achieved, and for a maximum of 16 weeks if complete remission is not achieved. 1, 2

• Adults generally receive lower doses on a per kilogram basis compared to children, which may explain the lower remission rate of only 50-60% with 8-week courses 1
• Increasing treatment duration to ≥16 weeks increases remission rates to 80% in adults 1
• After achieving remission, prednisone should be tapered slowly over a total period of up to 6 months 2
• The initial high dose should be maintained for a minimum of 4 weeks if complete remission is achieved 1, 2

Initial Treatment in Children

Children with MCD should receive prednisone 60 mg/m²/day (maximum dose) for 4-6 weeks, followed by 40 mg/m²/day on alternate days for 2-5 months. 1

• Approximately 95% of children achieve urinary remission within 4 weeks and complete remission after an 8-week course 1
• Increasing the duration of corticosteroid therapy to a total of 12 weeks improves the rate of sustained remission 1, 3

Common Pitfall: Steroid Toxicity

Prolonged glucocorticoid therapy entails increased risk of steroid toxicity, including:

• Glucose intolerance and diabetes 1
• Cushingoid features 1
• Infections 1
• Hip osteonecrosis (particular risk in elderly patients and post-menopausal women) 1

Treatment of Relapses

Infrequent Relapses

For infrequent relapses, use the same initial dose and duration of corticosteroids as for the first episode. 1, 2

• More than half of all patients who are initially steroid responsive experience relapses of their nephrotic syndrome 1
• Relapse is defined as proteinuria >3.5 g/day occurring after complete remission has been obtained for >1 month 1

Frequent Relapses

For patients with frequent relapses (≥2 episodes within 6 months), give daily prednisone until remission (at least 3 days), followed by alternate-day prednisone for at least 3 months. 1, 2

• Those who relapse frequently have a greater risk of becoming steroid-dependent 1
• Frequent relapsers are defined as having 2 or more relapses within 6 months 1

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

For frequently relapsing or steroid-dependent MCD, alternative therapies are required to avoid prolonged corticosteroid exposure and include cyclophosphamide, calcineurin inhibitors (CNIs), rituximab, or mycophenolic acid analogs. 1

Cyclophosphamide

In children, cyclophosphamide 2.0-2.5 mg/kg/day given for 8-12 weeks is usually well tolerated, with children with frequently relapsing nephrotic syndrome achieving longer remissions than those with steroid dependency. 1

• In adults, cyclophosphamide should be tried after a 12-week course before considering cyclosporin 1
• Cytotoxic therapy is effective in steroid-sensitive adults, with complete remission reported in 81% of cases and partial remission in a further 8% 1
• Exposure to cyclophosphamide should be minimized, especially in women at risk for amenorrhea and infertility or men planning to father children 1

Calcineurin Inhibitors (Cyclosporine and Tacrolimus)

Cyclosporin is recommended for adults who are steroid-resistant or steroid-dependent, or in patients with steroid toxicity or in whom steroids are contraindicated. 1

Cyclosporine Dosing and Monitoring:

• Start at 2 mg/kg/day and gradually increase at 2-week intervals until remission is achieved or the dose reaches 5 mg/kg/day or toxicity occurs 1
• Target 12-hour trough level of 60-150 ng/ml in children 1
• Following 3 months of stable remission, taper very slowly to reach the minimum dosage that maintains remission 1
• Cyclosporin should be continued for at least 12 months in children, as most will relapse upon discontinuation 1
• In adults, continue for 1-2 years after complete remission, tapering to a minimum dose target of ≤2 mg/kg/day 1

Tacrolimus Dosing:

• Start at 0.1 mg/kg/day given in two divided doses 1
• Target 12-hour trough level of 5-10 ng/ml, aiming for lowest levels to maintain remission and avoid toxicity 1
• Tacrolimus monotherapy at 0.05 mg/kg twice daily can be an effective alternative treatment for patients wishing to avoid steroid therapy, with 68% achieving complete remission at 8 weeks and 88% at 26 weeks 4

Critical Cyclosporin Considerations:

The prescribing physician should specify the exact brand of cyclosporin to be dispensed, as generic formulations show considerable variation in pharmacokinetic parameters. 1

• Cyclosporin is a "critical-dose drug" where small changes in dose or plasma concentration may result in clinically significant changes in efficacy and/or toxicity 1
• Brand switching or brand mixing could reduce efficacy or increase toxicity 1
• Patients should be educated about generic drug substitution and alert clinicians if a different formulation is obtained 1

Monitoring for Nephrotoxicity:

Adults continuing on long-term cyclosporin therapy should be regularly monitored, including consideration of repeat renal biopsy at 12-24 months to check for histological evidence of nephrotoxicity, especially if serum creatinine is >30% above baseline and/or if the maintenance dose required is >3.5 mg/kg/day. 1

• The acquired experience indicates that in most cases of MCD, the renal toxicity of cyclosporin is low, characterized by a few stripes of interstitial fibrosis 1

When to Stop CNI Therapy:

If an adult remains non-responsive to cyclosporin after 6 months of therapy, it should be stopped and a repeat renal biopsy carried out to confirm or refute the initial diagnosis. 1

Rituximab

Rituximab may be considered for frequently relapsing/steroid-dependent MCD, particularly in patients who have failed other second-line therapies. 1

• Patients treated with rituximab may be less likely to require a change of therapy and more likely to come off immunosuppressive drugs, with median time to relapse of 66 months versus 28 months in non-rituximab groups 5
• During last-line treatment, rituximab showed median time to relapse of 48 months versus 34 months in non-rituximab groups 5

Mycophenolate Mofetil/Mycophenolic Acid

Mycophenolate mofetil or mycophenolic acid analogs can be used for frequently relapsing/glucocorticoid-dependent MCD. 1

• However, low-dose prednisone (0.5 mg/kg/day) plus enteric-coated mycophenolate sodium 720 mg twice daily was not superior to standard high-dose prednisone (1 mg/kg/day) for inducing complete remission in adults 6
• This suggests mycophenolate is better suited as a steroid-sparing agent rather than as initial therapy 6

Special Clinical Situations

Contraindications to Corticosteroids

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

• A rare but important example is the pregnant woman with MCD, where high-dosage corticosteroids are hazardous to both mother and fetus, while cyclosporin is less harmful 1

Acute Kidney Injury

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

Adjunctive Therapies NOT Recommended

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. 1, 2

Treatment Algorithm Summary

For Initial Episode:

1. Start high-dose prednisone 1 mg/kg/day (max 80 mg) in adults or 60 mg/m²/day in children 1, 2
2. Continue for minimum 4 weeks if remission achieved, maximum 16 weeks if not 1, 2
3. Taper slowly over 6 months after remission 2

For Infrequent Relapses:

1. Repeat same initial corticosteroid regimen 1, 2

For Frequent Relapses/Steroid Dependence:

1. First consider cyclophosphamide 2.0-2.5 mg/kg/day for 8-12 weeks 1
2. If cyclophosphamide fails or produces non-durable remission, use CNI (cyclosporine 2-5 mg/kg/day or tacrolimus 0.1 mg/kg/day) 1
3. If CNI fails or causes toxicity, consider rituximab 1, 5
4. Mycophenolate can be used as steroid-sparing agent 1

For Steroid-Resistant Disease:

1. Use CNI as second-line therapy 1
2. If no response after 6 months, stop CNI and perform repeat biopsy 1

Key Monitoring Parameters

• Monitor for steroid-related side effects during treatment and tapering 2
• Check CNI trough levels regularly to ensure therapeutic range and avoid toxicity 1
• Monitor serum creatinine; if >30% above baseline on CNI, consider dose reduction or repeat biopsy 1
• Monthly dipstick surveillance to detect possible relapse 1

Prognosis

The risk of ESRD in MCD is extremely low, and long-term kidney survival is excellent in patients who respond to glucocorticoids. 1

• During median follow-up of 81 months in one study, no patients developed end-stage renal disease 5
• Relapse is frequent in adult MCD, with 52.1% experiencing at least one relapse during median observation of 37.6 months 7