Membranoproliferative Glomerulonephritis (MPGN)

Harrison's Principles of Internal Medicine, 22nd Edition

Pehle Samjho - MPGN Kya Hai? (What Is It?)

"MPGN is now considered a pattern of glomerular injury characterized by mesangial and subendothelial immune complexes, complement deposits and/or monoclonal protein deposits, or chronic endothelial cell injury."

• Harrison's 22E, p. 2464

MPGN Ka Core Structural Change (Microscopy)

1. Subendothelial deposits - endothelial cell aur GBM ke beech immune complexes/complement jam jaate hain
2. Mesangial interposition (Tram-tracking) - mesangial cells GBM aur endothelium ke beech ghus jaati hain, double contour banaati hain - yahi "tram-track" appearance hai on PAS/silver stain
3. Widened mesangium + hypercellularity - macrophages aur mesangial cells badh jaate hain

MPGN Kaise Hota Hai? - Pathogenesis (3 Major Mechanisms)

Mechanism 1: Immune Complex-Mediated MPGN

• Cryoglobulinemia (specially Hepatitis C se)
• Infection-associated GN (bacterial endocarditis, shunt nephritis)
• Hepatitis B and C
• Lupus (SLE) - class III/IV nephritis

1. Circulating immune complexes (antigen + antibody) form hote hain blood mein
2. Ye complexes glomerular capillary wall ke subendothelial space mein trap ho jaate hain
3. Complement activate hota hai (classical pathway via C1q)
4. C3 convert hoti hai, inflammatory mediators release hote hain
5. Mesangial cells aur macrophages migrate karke deposits ko clear karne ki koshish karte hain
6. Ye mesangial interposition GBM ko split kar deti hai - double contour (tram-track)

Mechanism 2: Complement-Mediated MPGN (C3 Glomerulopathy)

• Dense Deposit Disease (DDD) - pehle MPGN Type II - primarily children aur young adults mein
• C3 Glomerulonephritis (C3GN) - older age group (mean age 30)

"Both are associated with the presence of a complement mutation believed to cause the kidney pathology, including mutations in the complement factor H regulatory (CFHR) protein genes."

• Harrison's 22E, p. 2464

1. Normal mein Factor H complement ko regulate karta hai - alternative pathway ko rok-rok ke chalata hai
2. CFHR gene mutations ya C3 nephritic factor (C3NeF - an autoantibody against C3 convertase) ki wajah se Factor H ka regulation fail ho jaata hai
3. Alternative complement pathway dysregulated/overactivated ho jaata hai
4. C3 continuously split hota rehta hai - serum C3 low, C4 normal (kyunki classical pathway affect nahi hoti)
5. C3 fragments GBM mein jam jaate hain bina immunoglobulin ke - yahi C3 glomerulopathy ki defining feature hai
6. DDD mein: C3 dense ribbons GBM ke andar form karte hain (seen on EM as dense osmiophilic deposits)
7. Inflammatory response - mesangial proliferation aur MPGN pattern develop hoti hai

• Immunofluorescence: Sole/dominant C3 staining, little to no IgG/IgM
• Light microscopy: mesangial proliferative ya MPGN pattern

• Partial lipodystrophy (fat tissue loss)
• Drusen bodies in retina
• C3 level low, C4 normal
• C3 nephritic factor positive (esp. DDD)

Mechanism 3: Monoclonal Immunoglobulin-Mediated MPGN

"Monoclonal immunoglobulin mediated diseases including light and heavy chain deposition diseases."

• Harrison's 22E, p. 2464

• Multiple myeloma
• Waldenstrom's macroglobulinemia
• MGUS (Monoclonal Gammopathy of Undetermined Significance)

• Monoclonal light chains ya heavy chains glomeruli mein deposit ho jaate hain
• Ye bhi same MPGN pattern produce karta hai
• Biopsy pe immunofluorescence mein kappa ya lambda restriction dikhi jaati hai

Genetic Mutations Ka Role (Harrison's 22E)

"Mutations in control of the complement pathway increasingly associate with various forms of membranoproliferative glomerulonephritis (MPGN) and C3 glomerulopathies including dense deposit disease, or atypical hemolytic-uremic syndrome (aHUS); type II partial lipodystrophy from mutations in genes encoding lamin A/C or PPARγ causes a metabolic syndrome associated with MPGN."

• Harrison's 22E, p. 2455

• CFHR gene mutations - complement factor H related proteins
• Lamin A/C / PPARγ mutations - type II partial lipodystrophy + MPGN

Clinical Presentation

• Proteinuria (may be nephrotic range)
• Hematuria (macro ya micro)
• Mixed nephrotic-nephritic picture
• Low serum C3 (especially in complement-mediated)
• Normal C4 (if alternative pathway is the culprit)
• C3 nephritic factor present (most DDD cases)

Treatment (Harrison's 22E)

"The optimal therapies remain undefined but include inhibition of the renin-angiotensin system, lipid lowering, steroids, and other immunosuppressants. Evidence suggests a benefit of therapy with eculizumab, a monoclonal antibody directed at C3, which is activated by C3."

• Harrison's 22E, p. 2464

• RAAS inhibitors - proteinuria reduce karo
• Steroids + immunosuppressants
• Eculizumab (anti-C5 monoclonal Ab) - C3 glomerulopathy mein
• Treat the underlying cause - agar hepatitis C hai to antivirals, infection hai to antibiotics

Summary Table