R8 Renal Immune Injury

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Author:
jknell
ID:
206009
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R8 Renal Immune Injury
Updated:
2013-03-09 17:49:47
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Renal II
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Description:
Immune injury of the glomerulus
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  1. Normal glomerulus
    • Normal EM and diagram of capillary loop (tuft)
    • Epithelial cells = podocytes
    • Podocyts have primary and secondary (foot processes) processes
    • Podocyte foot processes are connected by proteins
    • "Slit diaphragm"
    • Mesangial matrix, mesangial cells are separated from blood only by the fenestrated endothelium
    • GBM does NOT separate mesangium from capillary
    • "Mes-angium" (middle, on the blood vessel)
  2. Classification of glomerular disease
    nephrotic vs nephritic
    • Nephrotic = proteinuria, low albumin, edema
    • -Ultrastructural alterations

    • Nephritic = hematuria, RBC casts, HTN, renal failure
    • -Inflammation, cell proliferation
    • -impaired filtration → elevated Cr
  3. Classification of glomerular nephritic disease
    • Immunological derangements:
    • -Primary glomerulonephritis
    • -Secondary glomerulonephritis

    • Genetic defects:
    • -Familial GN's

    • Othermetabolic disorders
    • -Diabetes
    • -Amyloid
    • -etc.

    • Etiology:
    • -immunological derangement → immunoglobulins and complement deposited in the glomeruli
    • -cell activation, cytokines, growth factors
    • → ultrastructure alterations, inflammation and cell proliferation
  4. Case 1:
    Acute renal failure; nephritic syndrome
    BUN 55, Cr 4
    Oliguria, with 1+ protein, moderate RBCs and RBC casts
    Bx:
    • Crescentic glomerulonephritis due to Anti-GBM antibody
    • IgG and C3 are found in a linear deposition pattern along the GBM
    • Bx shows inflammation (cells out into bowman's spcae); started as macrophages
  5. Case 2
    50 yr old with pitting edema feet, ankles
    Urine: 4+ protein, no cells
    BUN 18, Cr 1.1, Albumin 2.9 (nl 3.8 to 4.5)
    No signs of symptomatic disease
    Nephrotic syndrome

    Bx:
    • Membranous glomerulonephritis (GN)
    • IgG and C3 deposition along GBM in granular pattern
    • Basement membrane is thickened, but no inflammation or increased cells
  6. Pathology techniques glomerular disease
    • Immunofluorescence (IF)
    • Ultrastructure, Electron microscopy (EM)
    • Histology, Light microscopy)
  7. Immunofluorescence microscopy
    Anti-IgG from case 1:

    • Linear pattern of deposition of IgG along GBM
    • Crescentic GN due to Anti-GBM antibody
  8. Immunofluorescence microscopy
    Anti-IgG from case 2:

    • Granular  pattern of deposition of IgG along GBM
    • Membranous GN
  9. IF patterns and associated immunopathogenesis
    • 1. Linear IF 
    • → Anti GBM Ab

    • 2. Granular IF
    • →Immune-complex deposition (antigen-antibody complex)
    • →Membranous GN
    • →Other mechanisms

    • 3. Negative IF
    • →No Ab or complement involved
  10. Anti-GBM nephritis
    etiology, pathogenesis, pathology, pathophysiology, clinical disease
    Etiology: unknown

    • Pathogenesis: Ab against GBM (usually IgG)
    • -reacts with non-collagenous domain (NC1) of alpha-3 chain of type IV collagen in GBM

    Pathology: linear Ig and C' in glomeruli; glomerular inflammation

    Pathophys: Reduced GFR, glomerular hemorrhage

    • Clinical disease: Renal failure, hematuria
  11. Anti-GBM nephritis
    associated disease
    • 50% have GN alone; 50% have GN + lung hemorrhage
    • "Goodpasture's syndrome"

    Pathology: Ig and C' in lungs; alveolar inflammation

    Pathophys: reduced gas exchange, lung hemorrhage

    Clinical: respiratory failure, hemoptysis
  12. Immune-complex deposition
    Etiology, Pathology, Pathophysiology, Clinical disease
    • Antigen-antibody complexes in circulation → Circulating immune complex (CIC) precipitate within glomerular filter system
    • -Antigen: (? infection)
    • -Antibody: (normal, response poorly regulated?)

    • Pathology: Granular Ig and C' in glomeruli
    • -Glomerular structural changes and inflammation

    Pathophys: Reduced GFR, protein leak, etc

    Clinical disease: renal impairment, nephrotic syndrome, etc
  13. Glomerular deposition size → outcome
    Ag:Ab ratio
    • Ag>>Ab → small deposit → solube C.I.C.; slow clearance of deposit
    • Ag>Ab → medium deposit →potentially nephritogenic
    • Ag=Ab → large deposit → insoluble C.I.C.; cleared by kupfer cells
    • Ag<<Ab →small deposit → Soluble C.I.C.; immune clearance
  14. Immune complex deposition
    Sites of deposit, causes

    • Subepithelial: In-situ Immune Complex formation ("planted antigen" or autoantibody)
    • Subendothelial: Circulating Immune Complexes (C.I.C.)
    • Mesangial: C.I.C
  15. Subepithelial deposition
    In-situ immune complex formation: mechanisms
    • 1. "planted antigen" mechanism
    • -microbial macromolecule (i.e. cell wall of Streptococcus)
    • -Post-streptococcal GN

    • 2. Autoantibody mechanism
    • -circulating antibodies bind to native podocyte antigen
    • -attach to GBM, enlarge → impair podocyte function and activate complement → proteinuria
    • -Membranous GN: podocyte antigen is Type-M Phospholipase A2 receptor (PLA2R) (in 70% of cases)
    • -congenital membranous nephropathy: antigen is Neutral endopeptidase (NEP)
  16. Mesangial uptake phenomenon
    • -Preformed complexes injected into circulation diffuse into the mesangial region
    • -Adhere to the ECM or mesangial cell receptors

    • C.I.C. deposition:
  17. Ig deposition in glomeruli
    summary: mechanism
  18. Electron microscopy
    patterns of deposits

    • Granular deposits of Ig and C' are also visible in E.M.
    • 1. Subepithelial:
    • -IgG + C3 typical of Membranous GN
    • -C3 ± IgG seen in Acute Post-Infectious GN
    • Subendothelial:
    • -IgG + C3 typical of MPGN Type 1, proliferative SLE GN, and other immune-complex GNs
    • 3. Mesangial:
    • -IgA + C3 typical of Mesangial IgA GN
    • -IgG + C' seen in SLE GN, and other immune-complex GNs
    • 4. Intra-membranousrare
    • -Ribbon-like deposit within GBM, containing C3: typical of MPGN type 2

    Linear deposits
    of Ig and C' are NOT seen on EM
  19. Structural changes within glomeruli
    • "Minimal" change
    • Membranous change
    • Proliferative change
    • Sclerotic change
    • Minimal change:
    • -podocyte foot-process effacement (or "fusion")
    • -albumin filtered into urinary filtrate

    *light microscopy usually normal
  20. Minimal change EM
  21. Membranous change
    • GBM is thickened outside: spikes
    • GBM is reduplicated on the inside
  22. Membranous GN
  23. Membranoproliferative GN
  24. Proliferative change
    • Mesangial proliferation
    • Extracapillary proliferation: "crescent formation"
    • Normal glomerulus
    • Mesangial proliferation
    • "Crescent" formation (extracapillary proliferation)
  25. Sclerotic change
    • Focal glomerulosclerosis (FSGN):
    • focal and segmental hyalinosis

    • Chronic GN:
    • -global sclerosis
    • **end-stage of glomerular destruction due to any cause
  26. Focal vs diffuse

    Global vs segmental

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