Minimal Change Disease (MCD)

Overview

Etiology

• Drugs: NSAIDs, lithium
• Malignancies: Hodgkin's lymphoma (classically), non-Hodgkin's lymphoma
• Infections
• Biologic agents: Interferon-alpha, pamidronate, IL-2
• Allergies/atopy (40% in children, 30% in adults)

Pathogenesis

1. T-cell dysfunction: Activated T cells may release circulating permeability factors (cytokines such as IL-13 and IL-4) that damage the glomerular capillary wall. T cell hybridomas from MCD patients secrete factors that provoke heavy proteinuria in rats.
2. CD80 overexpression: Podocytes in MCD show overexpression of CD80 (B7.1), normally expressed by dendritic cells/B cells. Urinary CD80 correlates with disease activity. Dysregulated interactions between CD80 on podocytes and CTLA-4 on T lymphocytes may perpetuate injury.
3. Angiopoietin-like-4 overexpression: Corticosteroids and N-acetyl-D-mannosamine can reduce this overexpression.
4. Anti-nephrin antibodies: A subset of MCD patients have autoantibodies against nephrin (a slit-diaphragm protein), pointing to an autoimmune mechanism. Immunofluorescence shows minimal IgG despite the antibodies being present.
5. Endothelial injury: The majority of MCD patients also show mild glomerular endothelial injury with circulating endothelial biomarkers, suggesting MCD is not purely a "podocytopathy."
6. B-cell involvement: Evidence includes successful treatment with anti-CD20 (rituximab).

Morphology / Histopathology

Light Microscopy

• Normal-appearing glomeruli - no proliferation, no sclerosis, no deposits (hence the name "minimal change")
• Tubules may show lipid droplet accumulation and protein reabsorption droplets from leaked proteins

Immunofluorescence

• Negative for immune deposits (IgG, IgA, IgM, complement)
• Occasionally small amounts of IgM in the mesangium

Electron Microscopy (Diagnostic)

• Diffuse effacement (fusion) of podocyte foot processes along virtually every capillary loop - the hallmark finding
• Vacuolization and microvillus transformation of the visceral epithelium
• No electron-dense deposits
• Normal glomerular basement membrane

Clinical Features

• Urinary sediment: Acellular (no RBC casts)
• Selective proteinuria (mainly albumin, minimal high-molecular-weight proteins) - especially in children
• Serum complement levels and serology are normal
• Hypoalbuminemia, hyperlipidemia, edema - the classic nephrotic tetrad

Diagnosis

• Children: Clinical diagnosis (biopsy not usually required for initial presentation) - treated empirically with steroids. Biopsy done only in non-responders.
• Adults: Kidney biopsy required to confirm diagnosis
• EM showing foot process effacement with no deposits on IF is diagnostic

Treatment

Initial Therapy

• Daily: 1 mg/kg/day (max 80 mg) OR
• Alternate-day: 2 mg/kg (max 120 mg)
• Taper after 2 months, total course 5-6 months
• Adults: Not considered steroid-resistant until failure after 16 weeks of treatment
• Children: >90% respond to a short course of corticosteroids

Relapse Management

• Infrequent relapses: Repeat prednisone course (similar to initial)
• Frequent relapses / Steroid-dependent / Steroid-resistant:
  • Rituximab - 1000 mg IV, repeated in 2 weeks (anti-CD20)
  • Cyclosporine - 3-5 mg/kg/day for 4 months (CNI; monitor trough levels)
  • Tacrolimus - 0.05-0.1 mg/kg/day
  • Mycophenolate mofetil (MMF) - 750-1000 mg twice daily
  • Cyclophosphamide - up to 2 mg/kg/day for 8 weeks (less preferred due to gonadal toxicity and marrow suppression)

Supportive Therapy (All nephrotic patients)

• ACE inhibitors / ARBs + SGLT2 inhibitors - to reduce proteinuria and preserve renal function
• Lipid-lowering agents - for hypercholesterolemia (cardiovascular risk)
• Diuretics - for edema (avoiding intravascular volume depletion)
• Anticoagulation - for hypercoagulable state if indicated

Prognosis

• Generally excellent
• Children: >90% respond to steroids; relapses in >2/3 of initial responders; relapse frequency decreases after puberty
• Adults: 75-85% respond to steroids; ~40% relapse by 1 year; ~70-75% of children relapse after first remission
• 50%+ of all patients experience relapses overall
• 10-20% become steroid-dependent
• Patients with progressive renal decline usually demonstrate FSGS on subsequent biopsy (not true MCD)
• Long-term prognosis is less favorable in adults when acute kidney injury or steroid resistance occurs

Key Distinguishing Points vs. FSGS