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.


TERMINOLOGY


Abbreviations



  • Membranoproliferative glomerulonephritis (MPGN)


Synonyms



  • Hypocomplementemic glomerulonephritis (GN)


  • Lobular GN


  • Mesangiocapillary/mesangiopathic GN


Definitions



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


ETIOLOGY/PATHOGENESIS


Infectious Agents



  • May occur after infection, particularly upper respiratory tract infection


Autoimmune



  • ± 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


CLINICAL ISSUES


Epidemiology



  • 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


Presentation



  • 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


Treatment



  • 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


Prognosis



  • 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


MACROSCOPIC FEATURES


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


MICROSCOPIC PATHOLOGY


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


ANCILLARY TESTS


Immunofluorescence



  • 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


DIFFERENTIAL DIAGNOSIS


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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