Anti GBM disease

1. ANTI-GBM DISEASE

2. Objectives:
 Epidemiology
 Pathogenesis
 Clinical Presentation
 Laboratory and Pathology Findings
 Treatment
 Prognosis

3. Epidemiology
 Acute GN due to anti-GBM antibody disease is
rare, estimated in <1 per million
 10-15% of RPGN cases
 Distribution 3rddecade -young males (renal +
lung) &
6thdecade-only lung

4.  Outbreaks and seasonal variation in incidence , noted
(Irish study)
 Infection association-Influenza A
 Environmental association-Cigarette smoking,
pulmonary infection volume overload ,hydrocarbon
inhalation-lung hemorrhage
 Induce Autoimmune response-Systemic small vessel
vasculitis, MN, Urinary obstruction
 ALENTUZUMAB(anti-CD52)-lymphocyte depleting
agent used in relapsing Multiple myloma-loss of
regulatoryT cells
 HLA association-Positive-DRB1*1501, DRB1*0401
Negetive-DRB1*07

5. Nomenclature
 Goodpasture’s Syndrome
RPGN+Alveolar haemorrage
 Goodpasture’s Disease
Autoantibody specific to α3(1v)NC1with RPGN or
alveolar hemorrhage or both
 Anti-GBM Disease
Anti-GBM antibodies specific for any component
 Pulmonary-Renal syndrome
Renal faliure+Lung faliure

6. Differential Diagnosis in Patients Presenting
Clinically with Pulmonary-Renal Syndrome
 NECROTIZINGSMALL-VESSELVASCULITIS
 PR3- and MPO-ANCA associated (MPA,WG,CSS)
 Anti-GBM disease
 Other vasculitides (Henoch-Schönlein purpura,SLE, cryoglobulinemia, drug
induced)
 CATASTROPHICANTI-PHOSPHOLIPIDSYNDROME
 RENAL FAILUREWITHVOLUMEOVERLOAD / CARDIAC FAILURE
 Chronic/acute glomerulonephritis, diabetes
 Atherosclerosis/hypertensive nephrosclerosis
 Microangiopathic renal failure/hemolytic uremic syndrome
 - RENAL FAILUREASSOCIATEDWITH PULMONARY INFECTION
 Legionella, mycoplasma, streptococcus
 Hemorrhagic fever with renal syndrome (eg, Hantavirus)
 - ENDOCARDITIS
 SIRS/SEPSISWITH MULTIORGAN FAILURE
 CARDIOVASCULAR (eg, renal artery stenosis)

7. Immuno-Pathogenesis
 Antibodies directed against an antigen intrinsic to
the GBM-NC1 domain of the alpha-3 chain of
type IV collagen
 Type IV collagen-triple helical structure alpha 3,4,5
 Basement membrane of Glomerular , Alveolar
hemorrhage ,Retina , Cochlea and choroid plexus
 Two principle autoantibody(B cell) epitopes –EA &
EB
 Epitope spreading- autoantibodies against alpha
4&5

8.  T cell may cause- cell mediatedGlomerular injury (in
absence of Humoral immunity)
 Active disease renal biopsy-T lymphocytes
 Auto reactiveT cell correlates with disease activity
 RegulatoryT cells (CD4/25+) that counter the effects
of auto reactive cells reduce the severity of lesions in
murine anti-GBM GN
 Raising Anti GBM antibodies predates clinical
disease by months-Torrance mechanism
 Sulfilimine crosslink-stabilize the ass. Of opposing
NC1 domains on collagen chain
 When disrupted hidden epitopes are exposed

9. Clinical Presentation
 80 % to 90%-RPGN
 40% t0 60%- RPGN +Alveolar Haemmoage
 Small minority of patients- Isolated Alveolar
Hemorrhage
 Systemic complaints typically absent
 Malaise, weight loss, fever, arthralgia
 May suggest concurrent vasculitis

10. Serology Testing
 Enzyme immunoassay or Bead-Based
fluorescence assay
 Western blotting (more sensitive)(not widely
available)
 Indirect Immunofluorescence(using normal
renal tissue)
 High sensitive Bio sensor assay
 IgG1 & IgG3
 10% patients do not have identifiable
Antibodies

11.  Direct Immunofluorescence – usually Ig
deposition ,10 to 15% wth IgM or IgA rarly IgA
alone
GOLD STANDERD-strong linear ribbon like
appearance
 Specific binding- Goodpastures , Alports after
transplantation
 Non specific binding-DM, Cadaver kidneys,
Light chain disease, Fibrillary
Glomerulopathy , SLE
 Linear C3 deposition 75% cases

12. Kidney biopsy sample immunofluorescence for IgG revealing
linear deposits along the glomerular basement membrane, and
weaker staining of Bowman’s capsule and tubular basement
membranes.

13. Renal Biopsey
 Crescent formation is the histopathologic hallmark
of anti-GBM disease
 95% of patients will have evidence of crescent
formation
 80% of patients >50% of glomeruli will be affected
 In severe disease, rupture of Bowman’s capsule, peri-
glomerular inflammation, progressing to granuloma
formation with multinucleate giant cells, may be
observed
 Interstitial fibrosis and tubular atrophy are
uncommon

14. Subendothelial deposits of circulating immune complexes most
common, with subepithelial deposits rarely seen.

15. Standard Treatment
 Plasmapheresis, to rapidly remove
pathogenic autoantibody
 Along with cyclophosphamide and
corticosteroids, to inhibit further
autoantibody production and to ameliorate
end-organ inflammation.
 The use of this combination of therapies was
first described in 1976

16. Plasma exchange
 Daily 4 L exchange with 5% human albumin
solution.
 Add fresh human plasma (300–600 ml) within 3
days of invasive procedure (e.g., kidney biopsy)
or in patients with alveolar haemorrhage.
 Continue for 14 d or until antibody levels are fully
suppressed.
 Monitor antibody levels regularly after cessation
of treatment because plasma exchange may
require reinstatement if antibody levels rebound.

17.  Cyclophosphamide
2–3 mg/kg per d given orally for 2–3 mo. Reduce
dose to 2 mg/kg in patients>55 yr.
Stop if leukocyte count falls to <4 × 109/L
 Corticosteroids-
Prednisolone 1 mg/kg per d (maximum 60 mg)
given orally.
Reduce dose weekly to 20 mg by 6 wk, then
gradually taper until complete discontinuation at
6–9 month.

18.  Immunoadsorption
Alternative form of extracorporeal therapy
More efficient than plasma exchange for the
removal of pathogenic autoantibody
Although conversely it may not remove pro
inflammatory or pro coagulant factors
 Rituximab
As either “add-on” to standard therapy or as a
substitute for cyclophosphamide in patients who are
intolerant

19. PROGNOSIS
 Presenting with creatinine values <5 mg/dl,
renal survival was 95% and 94% at 1 and 5
years
 Presenting with creatinine > 5 mg/dl, but not
requiring immediate dialysis, renal survival
was 82% and 50%
 Presenting with an initial requirement for
dialysis, however, renal recovery occurred in
only 8% at 1 year

20. PREDICTORS OF POOR RENAL OUTCOME
 Severity of renal dysfunction at presentation
 The proportion of glomeruli affected by
crescents
 Oligoanuria at presentation
Hammersmith series
Patient who required hemodialysis and had
100% crescents on kidney biopsy did not recover
renal function
Withholding treatment is often considered in
these cases

21. Relapse
 Rare in anti-GBM disease
 Associated with ongoing exposure to
pulmonary irritants such as cigarette smoke
and hydrocarbons
 Repeat kidney biopsy in cases of relapse
 In confirmed cases, standard retreatment
with cytotoxics and corticosteroids is usually
indicated
 Multiply relapsing alveolar hemorrhage we
have found treatment with rituximab
beneficial.

22. Kidney Transplantation after
Anti-GBM Disease
 High chance of recurrence in the allograft, at
frequencies of up to 50%
 A recommend period of at least 6 months’
sustained seronegativity before undertaking
transplantation

23. Post-Transplant Anti-GBM
Disease in Alport Syndrome
 Mutations in the COL4A5 gene located on the X
chromosome are most common
 Autosomal recessive and dominant disease are
recognized with COL4A3 and COL4A4 mutations
 After kidney transplantation, these patients may develop
anti-GBM antibodies-
Alloimmune response to the neo-antigens
contained in “normal” α3, α4, or α5 chains in the kidney
allograft
 GN develops early and carries a high risk of graft loss

24. Double-Positive Anti-GBM and
ANCA-Associated GN
 50% of patients with anti-GBM disease have
detectable ANCA (usually recognizing
myeloperoxidase [MPO])
 10% of patients with ANCA also have circulating
anti-GBM antibodies
 ANCA-induced glomerular inflammation may be
a trigger for the development of an anti-GBM
response
 Relapsed at a higher frequency

25. Anti-GBM Disease Associated with
Membranous Nephropathy
 A rapid decline in kidney function in a patient
with known membranous nephropathy
should raise suspicion of the development of
superimposed crescentic nephritis or anti-
GBM disease
 Rebiopsy is recommended
 Rituximab may be a useful

26.  Fostamatinib
A spleen tyrosine kinase (SYK)
inhibitor, effectively reverses crescent formation
in rodent models
 IdeS (IgG-degrading enzyme of Streptococcus
pyogenes)
An enzyme that is able to cleave both
circulating and membrane-bound Ig
safe and tolerable in early-phase human
studies

27. THANK YOU..