Membranoproliferative Glomerulonephritis, Type I/III

Membranoproliferative Glomerulonephritis, Type I/III

A. Brad Farris, III, MD

MPGN, type I shows exuberant mesangial hypercellularity, which gives a lobulated appearance and capillary wall thickening, as shown here in a 10-year-old boy with hematuria, proteinuria, and low C3.

By EM, MPGN, type I shows numerous subendothelial electron-dense deposits image along the GBM image and new GBM layers image, giving a “tram track” appearance in PAS or silver stains.



  • Membranoproliferative glomerulonephritis (MPGN)


  • Hypocomplementemic glomerulonephritis (GN)

  • Lobular GN

  • Mesangiocapillary/mesangiopathic GN


  • Subendothelial electron-dense deposits with mesangial interposition between capillary wall and GBM with clinical finding of hypocomplementemia


Infectious Agents

  • May occur after infection, particularly upper respiratory tract infection


  • ± C3 nephritic factor, IgG autoantibody, or other autoantibodies, resulting in persistent activity of alternative complement pathway (˜ 25% of MPGN type I patients)

Immune Complex Deposition

  • Circulating immune complexes present in many MPGN, type I patients

  • Activates classical & alternative complement pathways

  • Chronic serum sickness caused by repeated injection of antigen resembles MPGN

Secondary Causes

  • Many different etiologies can lead to 2° MPGN-type pattern

  • Therefore, 1° MPGN is a diagnosis of exclusion



  • Incidence

    • ˜ 5% of GN in children and adults

  • Age

    • Primarily older children, adolescents, and young adults (˜ 7-30 years old)

      • Rare in children < 2 years old or adults > 50 years old

  • Gender

    • Approximately equal male:female ratio

  • Ethnicity

    • Reportedly higher incidence in whites

    • Navajo Indians in USA may have high rates of nondiabetic ESRD due to GN of this type


  • Nephrotic syndrome

    • Occurs in > 50% of patients

    • Predominant feature in 2/3 of patients

  • Proteinuria

    • May be subnephrotic

    • Syndrome often initially nephritic & eventually nephrotic

  • Hypocomplementemia

    • Low C3 as in other types of MPGN

    • Low classic pathway components (C1, C2, and C4), Factor B, and properdin

    • ˜ 80% of MPGN, type I; ˜ 100% of MPGN, type II; & ˜ 50% of MPGN, type III

  • Hematuria

    • ± recurrent episodes of gross or microscopic hematuria

    • Acute nephritic syndrome in 10-20%

  • Hypertension

    • Usually mild but may be malignant

    • ˜ 1/3 of patients

  • Renal vein thrombosis may be present

Laboratory Tests

  • Complement often decreased, as above

    • In type I MPGN

      • ↓ C3 & total hemolytic complement (CH50) in 50%

      • C1q, C4, properdin, & factor B borderline/↓ in < 50%

    • In type III MPGN

      • ↓ C3, normal C4

      • ↓ C5, C6, C7, and C9 levels may be 2° to terminal pathway nephritic factor

  • C3 nephritic factor (common in type II MPGN)

    • Present in ˜ 25% of type I MPGN patients & absent in type III MPGN


  • Drugs

    • Steroids

      • Long-term, low-dose steroids used in children with 1° MPGN (lead to growth retardation & hypertension)

      • Repeat biopsy often performed within 5 years of therapy initiation to ascertain if continued therapy is needed

    • Antiplatelet agents (dipyridamole & aspirin) used alone or with steroids


  • Variable but usually poor with persistent proteinuria

    • Classically a chronic, slowly progressive course

  • 5-20% have clinical remission

  • Survival has been measured at ˜ 50% at ˜ 10 years

    • Median renal survival time in MPGN, type I: 9-12 years, compared with MPGN, type II: 5-12 years

    • Prognosis of patients with MPGN, type III is similar to that of patients with MPGN, type I

    • Therapy improves survival to 60-85% at 10 years

  • Prognostic features of poor outcome

    • Sclerotic glomeruli, crescents, interstitial fibrosis, & tubular atrophy (IF/TA)

  • Clinical features of poor outcome

    • Severe nephrotic syndrome, ↑ creatinine, hypertension

  • Features of good outcome

    • Focal/mild MPGN features on biopsy, asymptomatic hematuria, subnephrotic proteinuria

  • ˜ 30% of children with MPGN, type I have recurrence in 6 months to 1 year after transplant

    • ˜ 40% of recurrences lead to graft failure


General Features

  • Nephrectomy, exam at transplant, or autopsy reveals pale kidneys

  • ± cortical yellow flecks, representing tubular lipid & interstitial foam cells

  • Advanced disease: Small granular kidneys ± prominent vessels


Histologic Features

  • Glomeruli

    • Lobular, hypercellular glomeruli with thickened capillary walls & ↑ mesangial substance

    • Mesangial interposition: Mesangial cells migrate into peripheral capillary walls between GBM & endothelium

      • Partial if only capillary wall segment involved

      • Circumferential if involving entire circumference of individual capillary

      • Produces “tram tracks” or GBM reduplication (best seen on PAS & silver) 2° to GBM synthesis

      • ± subendothelial immune deposits (between duplicated GBMs) seen by light microscopy (PAS[+], nonargyrophilic on silver, & fuchsinophilic on trichrome)

    • ± sclerosis; ± sclerotic mesangial nodules

    • Crescents in ˜ 20% of cases

    • ± neutrophils & monocytes

    • Hyaline aggregates of immune complexes in capillary lumina

    • Type III: Burkholder variant

      • Combined features of type I MPGN & membranous GN

      • Glomerular capillary loops markedly thickened due to subendothelial & subepithelial deposits & mesangial interposition

      • Mesangial expansion with exudation of inflammatory cells

    • Type III: Anders and Strife variant

      • Hybrid of type II (dense deposit disease) & type I MPGN

      • Glomerular capillary walls have an irregular thickening that is eosinophilic, PAS(+), silver (JMS) (-)

      • Silver stains show frayed GBM with disrupted, “moth-eaten” appearance

  • Tubulointerstitium

    • Largely nonspecific with variable interstitial fibrosis and tubular atrophy, inflammation, & edema

    • Tubular resorption droplets

    • Interstitial foam cells

    • Red cell casts

  • Vascular changes nonspecific



  • MPGN, type I

    • C3 in capillary walls & mesangium is classic feature

      • To lesser extent, IgG present followed by IgM, IgA, & C1q

      • Up to 25% have C3 only and would now be classified as C3 glomerulopathy

    • Also “lumpy-bumpy” granular C3, IgG, & early complement (C1q & C4)

    • “Railroad track” pattern may be seen on IF at high power

    • Focal C3 deposits in the TBM

  • MPGN, type III subtypes have similar findings

    • ˜ 50% of cases have IgG & C3 (& less intense IgM, IgA, & C1q)

    • ˜ 50% stain only for C3

    • Focal TBM C3 staining is present in ˜ 1/3 of cases

Electron Microscopy

  • Transmission

    • Large, dense deposits throughout glomerulus; primarily subendothelial but also mesangial

      • Produces double GBMs with mesangial interposition

      • GBM has a “sausage-string” or fusiform appearance

      • Intramembranous dense deposits in GBM reflections

      • Increased mesangial matrix

    • “Mesangialization” of capillary loops

    • Podocyte foot process effacement

    • Type III: Burkholder variant

      • Combined features of MPGN, type I & membranous glomerulonephritis

      • Subendothelial deposits & mesangial interposition

    • Type III: Anders and Strife variant

      • Hybrid of MPGN, type II (also known as dense deposit disease) & MPGN, type I

      • Subendothelial & intramembranous deposits

      • Deposits extend from GBM subendothelial to subepithelial portion, disrupting GBM lamina densa, giving a laminated, woven appearance

      • TBM deposits present in ˜ 1/3 of cases

      • Initially described using silver impregnation techniques


Systemic Lupus Erythematosus (SLE)

  • IF shows “full house” staining pattern

  • Serology(+) in SLE: ANA(+), anti-ds DNA(+)

Mixed Cryoglobulinemia

  • Mixed cryoglobulinemia associated with chronic hepatitis C has been associated with number of cases of MPGN, type I

  • Characteristic PAS(+) “pseudothrombi” can be seen in glomerular capillary loops in cryoglobulinemic GN

  • Clinical laboratory can help identify cryoglobulin

Infectious Diseases

  • History, physical, & clinical laboratory data can help favor diagnosis of infectious disease

  • Bacterial

    • Endocarditis & infected vascular shunts

    • Post-streptococcal acute glomerulonephritis: Elevated antistreptolysin-O (ASLO) titers

  • Viral: Hepatitis B & C, HIV

  • Protozoal: Malarial & schistosomiasis

  • Other: Mycoplasma, mycobacteria

Jul 7, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Membranoproliferative Glomerulonephritis, Type I/III

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