ANTI GBM DISEASE

INTRODUCTION
• Most recent version of the Chapel Hill nomenclature of vasculitis the
disease entity “Anti-glomerular basement membrane disease” (anti-
GBM-disease) is included among immune complex small vessel
vasculitides

• Definition - vasculitis affecting glomerular capillaries, pulmonary

capillaries, or both, with GBM deposition of anti-GBM
autoantibodies.

• Lung involvement causes pulmonary haemorrhage, and renal

involvement causes glomerulonephritis with necrosis and crescents.
• 10% to 20% of crescentic glomerulonephritides

• Characterized by circulating antibodies to the GBM (anti-GBM)

and deposition of IgG or, rarely, IgA along the GBM

• 2 forms - Renal-limited disease (antiGBM glomerulonephritis)

and as a pulmonary-renal vasculitic syndrome (Goodpasture’s
syndrome)

• Incidence of anti-GBM disease has two peaks with

respect to age
• First peak is in the second and third decades of life, and anti-GBM disease
in this age group shows a higher frequency of pulmonary hemorrhage
(Goodpasture’s syndrome)

• Second peak is in the sixth and seventh decades, and this later-onset
disease is more common in women, who more often have renal-limited
disease

• Development of the autoimmune response prior to onset of disease -

History
• 1919: Goodpasture described the case of an 18-yo man who died
with lung hemorrhage and acute GN

• 1958: Clinical picture of pulmonary renal syndrome described by

Stanton and Tage and named after Dr. Goodpasture

• Anti-GBM antibodies discovered in 1967

• Lerner, et al. conducted famous studies with antibodies eluted from the
serum of Goodpasture’s patients transferred to monkeys who developed
proliferative GN
 Chelsea Naval Hospital
Circa 1918

Dr. Ernest Goodpasture

1955
Vanderbilt Laboratory

1919—looking at pathologic
features of influenza in the lung

patient with systemic disease

and pulmonary + renal involvement
 Table 1 Differential Diagnosis in Patients Presenting Clinically
with Pulmonary-Renal Syndrome

- NECROTIZING SMALL-VESSEL VASCULITIS

* PR3- and MPO-ANCA associated (MPA, WG, CSS)
* Anti-GBM disease
* Other vasculitides (Henoch-Schönlein purpura, SLE, cryoglobulinemia, drug
induced)
- CATASTROPHIC ANTI-PHOSPHOLIPID SYNDROME
- RENAL FAILURE WITH VOLUME OVERLOAD / CARDIAC FAILURE
* Chronic/acute glomerulonephritis, diabetes
* Atherosclerosis/hypertensive nephrosclerosis
* Microangiopathic renal failure/hemolytic uremic syndrome
- RENAL FAILURE ASSOCIATED WITH PULMONARY INFECTION
* Legionella, mycoplasma, streptococcus
* Hemorrhagic fever with renal syndrome (eg, Hantavirus)
- ENDOCARDITIS
- SIRS/SEPSIS WITH MULTIORGAN FAILURE
- CARDIOVASCULAR (eg, renal artery stenosis)
 PATHOGENESIS

• Landmark studies opening the way to an understanding of the pathogenesis of

anti-GBM disease were those of Lerner, Glassock, and Dixon

• Antibodies eluted from kidneys of patients with Goodpasture’s syndrome and

injected into monkeys  glomerulonephritis, proteinuria, renal failure, and
pulmonary hemorrhage along with intense staining of the GBM for human IgG

• Antigen to which anti-GBM antibodies react collagenase-resistant part of type IV

collagen, the noncollagenous domain (NC1 domain)

• 90% of anti–type IV collagen antibodies are directed against the α3-chain of type
IV collagen
 • The alpha-3 chain forms a triple helix with alpha 4/5 chains,
combining with another triple helix to form a hexamer

• Antigenic epitopes found in the NC1 domain are in a cryptic form,

little reactivity is found against the native hexameric structure of
the NC1 domain.

• However, when the hexameric NC1 domain is denatured and

dissociates into dimers and monomers, the reactivity of antibodies
increases 15-fold
• Anti-GBM autoantibodies react with epitopes on the noncollagenous
domain of the α-3 and -5 chains of type IV collagen.

• . The α-3 chain of type IV collagen is found predominantly in the GBM and
alveolar capillary basement membranes, which correlates with the limited
distribution of disease involvement in Goodpasture’s syndrome
• It is presumed that environmental factors, such as exposure to hydrocarbons,
tobacco smoke,and endogenous oxidants, can also expose the cryptic Goodpasture
epitopes

• Small percentage of patients with anti-GBM disease may also have limited
reactivity with the NC1 domains of the α1- or α4-chains of type IV collagen

• Majority of patients with anti-GBM disease antibodies to two major

conformational epitopes (EA and EB) located within the C-terminal noncollagenous
(NC1) domain of the α3-chain of type IV collagen.

• The immunodominant target epitope, EA, is encompassed by

α3 NC1 residues 17 to 31 A / residues 127 to 141 encompasses the EB epitope,
recognized by the autoantibodies of only a small number of patients
• Antibody levels against α3, EA, and EB correlated with serum creatinine level and
with death or ESKD at 1 year

• One third of patients with anti-GBM/Goodpasture’s syndrome also have circulating

ANCAs, the majority being to MPO (MPO-ANCA)

• Mechanism by which some patients develop both anti-GBM antibodies and ANCAs
is unknown  ANCAs may appear first and cause damage to the GBM, thus
exposing the normally hidden target epitopes of anti-GBM antibodies

• Coexistence of ANCAs in patients with anti-GBM antibodies is associated

with small vessel vasculitis in organs in addition to the lung and kidney.
• Anti-GBM alloantibodies that cause posttransplant nephritis in some patients
with X-linked Alport’s syndrome are directed against conformational epitopes in
the NC1 domain of α5(IV) collagen .

• Mainly target two epitopes accessible in the α3α4α5 NC1 hexamers of human
GBM, unlike the sequestered α3 NC1 epitopes of anti-GBM autoantibodies.

Role of T-cell mediated immunity - anti-GBM disease is considered a prototypical

antibody-mediated glomerulonephritis, important role for T cells in the initiation
or pathogenesis of this disease

• Suggested by the increased susceptibility to the disease associated with the

presence of HLA class II antigens DRB1*1501 and DQB*0602

• Experimental studies - transfer of CD4+T cells specific to a recombinant

GBM antigen into syngeneic rats resulted in a crescentic glomerulonephritis
without linear anti-GBM IgG deposition

• CD4+CD25+ regulatory T cells may play an important role in regulating the

immune response in anti-GBM disease.
• Experimental Studies : Transfer of regulatory T cells into mice that were
previously immunized with rabbit IgG, and before an injection of anti-GBM rabbit
serum, significantly attenuated the development of proteinuria and dramatically
decreased glomerular damage

• Action of regulatory T cells may explain, uncommon occurrence of disease

relapses and the eventual disappearance of anti-GBM antibodies in patients even
without the use of immunosuppressant medications

Role of complements :

• Evidenced by the deposition of C3 along the GBM

• Animal models - Albuminuria was absent in Fcγ chain–deficient mice and

reduced in C3-deficient mice
C1q- and C4-deficient mice did develop proteinuria, which is suggestive of
involvement of the alternative complement pathway
GENETICS

• Genetic susceptibility to anti-GBM disease is associated with HLA-DR2 specificity

• Detailed analysis of the association with HLA-DR2 revealed a link with the DRB1
alleles, DRB1*1501 and DQB*0602
 PATHOLOGY

LM
• 97% of patients with anti-GBM disease have some degree of crescent formation, and
85% have crescents in 50% or more of glomeruli

• Glomeruli with crescents typically have fibrinoid necrosis in adjacent glomerular

segments

• Nonnecrotic segments may look entirely normal by light microscopy or may have
slight infiltration by neutrophils or mononuclear leukocytes.

• This differs from crescentic immune complex glomerulonephritis and C3

glomerulopathy, which typically have capillary wall thickening and endocapillary
hypercellularity in the intact glomeruli.

• Jones’ methenamine silver stain or periodic acid–Schiff stain, often demonstrate

focal breaks in GBMs in areas of necrosis and also show focal breaks in Bowman’s
capsule.
• Acute necrotizing glomerular lesions and the cellular crescents evolve into
glomerular sclerosis and fibrotic crescents, respectively.

• Kidney biopsy  several weeks into the course of anti-GBM disease chronic
sclerotic lesions.

• Glomeruli with extensive necrosis and disruption of Bowman’s capsule typically have
intense periglomerular inflammation, including occasional multinucleated giant cells

• Necrotizing inflammation in arteries or arterioles,  concurrent anti-GBM and ANCA

disease should be considered.
FIGURE Anti–glomerular basement membrane disease (Goodpasture’s
syndrome). There is diffuse crescentic glomerulonephritis with large
circumferential cellular crescents and severe compression of the
glomerular tuft (periodic acid–Schiff, ×80).

Brenner and Rector’s The Kidney

 IF

• Linear staining of the GBMs for immunoglobulin is indicative of anti-GBM

glomerulonephritis

• Immunoglobulin is predominantly IgG; however, rare cases of patients with IgA

dominant anti-GBM glomerulonephritis have also been reported

• Discontinuous linear to granular capillary wall staining for C3, but a minority
show little or no C3 staining.

• Two other disorders in which linear IgG staining can be seen in the glomeruli:
diabetic nephropathy and fibrillary glomerulonephritis.
In the former and in the latter, the IgG is nonspecifically absorbed onto the
highly permeable glomerular capillary wall and onto the fibrils, respectively.

• Staining is rarely as strong as with antiGBM disease .

• In diabetic nephropathy, there is also linear deposition of albumin and
other plasma proteins

• Circulating antiGBM antibodies are absent in both disorders, and crescents

are not seen in diabetic nephropathy.

• Finding of diabetic glomerulosclerosis on light microscopy, and, in fibrillary

glomerulonephritis, the presence of the characteristic fibrils on electron
microscopy – differentiating feature
 FIGURE 32-22 Anti–glomerular basement membrane disease
(Goodpasture’s syndrome). Immunofluorescence photomicrograph
showing linear glomerular basement membrane deposits of
immunoglobulin G. Some of the glomerular basement membranes are
discontinuous, indicating sites of rupture (×800).

Brenner and Rector’s The Kidney

ELECTRON MICROSCOPY

Reflect those seen by light microscopy

Acute disease focal glomerular necrosis with disruption of capillary walls. Bowman’s
capsule also may have focal gaps. Leukocytes, including neutrophils and monocytes,
often are present at sites of necrosis

• Fibrin tactoids, which are electron-dense curvilinear accumulations of polymerized

fibrin, accumulate at sites of coagulation system activation, including sites of
capillary thrombosis, fibrinoid necrosis, and fibrin formation in Bowman’s space

• Important negative observation is the absence of immune complex–type electron-

dense deposits.

• Chronic lesions  amorphous and banded collagen deposition distorts or replaces

the normal architecture.
 CLINICAL FEATURES AND NATURAL HISTORY

• Renal anti-GBM disease is typically characterized by an abrupt, acute glomerulonephritis

with severe oliguria or anuria

• High risk of progression to ESRD if appropriate therapy is not instituted immediately

• Patient survival of approximately 85% and renal survival of approximately 60% with
treatment

• Onset of disease may be associated with arthralgias, fever, myalgias, and abdominal
pain

• Goodpasture’s syndrome presence of pulmonary hemorrhage concurrent with

glomerulonephritis (40-60 %)
• Absence of hemoptysis does not rule out diffuse alveolar hemorrhage - presence
of unexplained anemia

• Diagnostic evaluation of alveolar hemorrhage usually includes bronchoscopic

examination and bronchoalveolar lavage

• Pulmonary hemorrhage is far more common in smokers than nonsmokers 

environmental exposures to hydrocarbons or upper respiratory tract infections.
 expose the cryptic antigen in the alveolar basement membrane, allowing its
recognition by circulating anti-GBM antibodies.
• Chest radiography extensive bilateral air-space consolidation.resolves within
23 days and is replaced by a reticulonodular pattern and interlobular septal
thickening

• Broncoalveolar lavage as gold standard Lazor et al. found the sensitivity to be

86% for chest X-ray, and results for high resolution computed tomography were
not better (80%)

• Serologic testing :

1. Indirect immunofluorescence is rarely performed and requires an experienced

renal pathologist.
- Involves incubation of the patient's serum with normal renal tissue.
- Fluorescein labeled antihuman IgG is then added to see whether IgG deposition
has occurred, and the results are compared with those obtained with normal
serum.
- The test has a high false negative rate,  40 percent
2. Direct enzymelinked immunoassay (ELISA)
More common approach by the detection of antiGBM antibodies in serum Specificity of
the antibody can be confirmed by Western blot

• High antibody titers are usually found in those with rapidly progressive disease.
• False negative results may occur in those with low antibody titers some patients with
Alport syndrome who develop posttransplant antiGBM disease, with antibodies
directed against the alpha5(IV) chain

• ELISA assays that use native or recombinant human alpha3(IV) antigen substrates
are much more sensitive and specific, sensitivity of 95 to 100 percent
and specificity of 91 to 100 percent

3. ANCA : 10 -38 percent of patients with antiGBM antibody disease also test positively
for ANCA (MPO- ANCA) at the time of diagnosis and may have signs of a systemic
vasculitis or a marked systemic inflammatory response

Low levels of ANCA may be detectable years before the production of antiGBM
antibodies and the onset of clinical symptoms
• The detection of ANCA is clinically relevant, as these patients may be more
likely to have treatable disease than those who have only antiGBM antibodies
 TREATMENT

• Important determinant of the response to therapy and longterm prognosis is early

diagnosis
• There is a direct correlation between the initial plasma creatinine concentration
and the percent of glomeruli with crescents;
• Crescents are present in more than 75 percent of glomeruli when the plasma
creatinine concentration is above 5 mg/dL

• Proportion of preserved glomeruli may be the best determinant of prognosis

Prognosis of untreated patients

Prognosis of untreated acute glomerulonephritis due to antiGBM antibody disease is

extremely poor
In a case series of 67 patients, death or dialysis in over 90 percent of patients
In another review of 32 patients with Goodpasture's syndrome, 29 progressed to
dialysis dependency.
• Reviews of available reports suggest that approximately 40 to 45 percent of patients
will benefit by not progressing to endstage renal disease or death, when treated with
plasmapheresis in combination with immunosuppression

• Recovery is much more likely in patients who begin treatment before oliguria ensues,

Plasmapheresis :

The only available randomized trial evaluated outcomes among 17 patients who were
treated with prednisone and cyclophosphamide alone, or with plasmapheresis

End of treatment, two of eight patients who received plasmapheresis, compared with
six of nine in the immunosuppression alone group, became dialysis dependent

Johnson JP, Moore J Jr, Austin HA 3rd, et al. Therapy of antiglomerular basement membrane antibody disease: analysis of
prognostic significance of clinical, pathologic and treatment factors. Medicine (Baltimore) 1985; 64:219.
Bolton WK. Goodpasture's syndrome. Kidney Int 1996; 50:1753.
Madore F, Lazarus JM, Brady HR. Therapeutic plasma exchange in renal diseases. J Am Soc Nephrol 1996; 7:367.
• Patients with less than 30 percent crescents and a plasma creatinine below 3 mg/dL
did well, while those with severe crescentic involvement and a plasma creatinine
above 4 mg/dL (354micromol/L) did poorly

• Large retrospective study of 221 patients from China reported better patient and
renal survival among those treated with plasmapheresis, glucocorticoids, and
cyclophosphamide compared with those who received glucocorticoids and
cyclophosphamide

• Improved morbidity and mortality in the era of plasmapheresis compared to historic

rates

• Greater amelioration of the consequences of disease with rapid removal of antiGBM

antibody, compared with a slower reduction in levels seen with immunosuppressive
agents

Cui Z, Zhao J, Jia XY, et al. Antiglomerular basement membrane disease: outcomes of different therapeutic
regimens in a large singlecenter Chinese cohort study. Medicine (Baltimore) 2011; 90:303.
• Daily or alternate day 4 liter exchanges for two to three weeks

• Albumin is given as the replacement fluid.

• Recent renal biopsy or has pulmonary hemorrhage, then one to two liters of fresh
frozen plasma should be substituted for albumin at the end of the procedure to
reverse pheresis induced depletion of coagulation factors

• Continued pheresis may be required if the patient still has active pulmonary
disease (eg, hemoptysis) or if antibody titers are not declining substantially

Immunosuppressive therapy

• Pulse methylprednisolone (15 to 30 mg/kg to a maximum of dose of 1000 mg

intravenously over 20 minutes) daily for three doses followed by daily oral
prednisone (1 mg/kg per day to a maximum of 60 to 80 mg/day), which can be
tapered once remission is induced.)

• Initial cyclophosphamide dose is 2 mg/kg per day oral

Rituximab : Patients who either refuse or, because of severe side effects, need to
discontinue cyclophosphamide may receive rituximab

DURATION OF THERAPY :

Spontaneous cessation of autoantibody formation can take six to nine months or

longer

After remission is induced, maintenance therapy with less toxic drugs, such as lowdose
prednisone and azathioprine should be given for six to nine months.

AntiGBM antibody levels should be monitored every one to two weeks until they are
negative on two occasions

If the antiGBM antibody titers remain positive after three to four months of therapy
with cyclophosphamide, prednisone alone or in combination with azathioprine (1 to 2
mg/kg per day, which is substituted for cyclophosphamide) should be
continued for six to nine months.
Syeda UA, Singer NG, Magrey M. Antiglomerular basement membrane antibody disease treated with
rituximab: A casebased review. Semin Arthritis Rheum 2013; 42:567.
Long term outcomes with treatment : Based on a retrospective review of 71 patients

- patients with a plasma creatinine concentration of < 5.7 mg/dL ,patient and renal
survival were 100 and 95 percent at one year and 84 and 74 percent at last follow up
(median period of 90 months)

- patients who presented with a plasma creatinine concentration greater than 5.7
mg/dL but who did not require immediate dialysis (within 72 hours of presentation),
patient and renal survival were 83 and 82 percent at one year and 72 and 69 percent
at last follow up

- patients who required immediate dialysis, patient and renal survival were 65 and 8
percent at one year and 36 and 5 percent at last followup, respectively
 Newer approaches : Immunoadsorption may be effective in antiGBM antibody
disease, even in dialysis dependent patients.
Combined use of immunosuppression and immunoadsorption using a sepharose-
coupled sheep antihuman IgG column for 25 cycles resulted in the recovery of
renal function, with a stable creatinine concentration of 2 mg/dL

KDIGO RECOMMENDATIONS

1. initiating immunosuppression with cyclophosphamide and corticosteroids plus

plasmapheresis in all patients with anti-GBM GN except those who are dialysis-
dependent at presentation and have 100% crescents in an adequate biopsy sample,
and do not have pulmonary hemorrhage.
TRANSPLANT