Overview of renal disease with anti-GBM involvement

1. Anti-GBM Diseases
Amanda Valliant, MD
Nephrology Fellow
11.28.12

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
 <20% of RPGN cases
 Bimodal distribution young males (3rd decade)
and older females (6th decade) most typical
 Disease limited to the kidney more common in
older patients
 Less common in blacks, likely due to HLA antigen
differences

4. Nomenclature
 Goodpasture’s Syndrome
• Used to describe clinical findings of GN and
pulmonary hemorrhage
 Goodpasture’s Disease
• Triad of proliferative GN (usually crescentic),
pulmonary hemorrhage, anti-GBM antibodies
 Anti-GBM Disease
• Anti-GBM antibodies + GN

5. 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

6. A lesson in 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

7. 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) Sanders, et al. 2011

8. Pathogenesis
 Antibodies directed against an antigen
intrinsic to the GBM
• Antibodies may precede clinical signs by
weeks or months
• Typically IgG1 or IgG3 antibodies
• Principal target is the NC1 domain of
the alpha-3 chain of type IV collagen

9. Varied Presentations of Anti-GBM
Disease
 In anti-GBM disease the pulmonary hemorrhage
may precede, occur concurrently with, or follow the
glomerular involvement
 Some patients with anti-GBM antibodies and GN
and hence “anti-GBM” disease never experience
pulmonary involvement and thus do not have true
“Goodpasture’s syndrome.” (perhaps 60%)
 Typical presentation is relatively acute renal failure
with urinalysis showing proteinuria and a nephritic
sediment
• Typically not nephrotic range proteinuria
• Dysmorphic RBCs, WBCs, red cell and granular casts

10. Clinical Presentation
 Systemic complaints typically absent
• Malaise, weight loss, fever, arthralgia
• May suggest concurrent vasculitis
 Relatively mild degree of renal involvement
may be more common than previously
thought
• Retrospective analysis in Australia found 36%
(5/14) had previous findings of hematuria and/or
proteinuria with normal creatinine

11. Antibodies bind tightly and
rapidly to the GBM, which
has been demonstrated in
passive transfer experiments
in which antibody obtained
from the plasma of patients
with the disorder are infused
into animals.
Titers of antibodies directed against
the N-terminus of the NC1 domain
correlate directly with renal survival.
Hellmark, et al. Kidney International, 1999.

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

13.  Anti-GBM autoantibodies react with epitopes on the
noncollagenous domain of the α-3 and -5 chains of type IV
collagen.
 The antigenic epitope has been localized between amino
acids 198 and 237 of the terminal region of the α-3 chain.
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
Cryptic epitope??

14. Pathogenesis: Antigen Structure
 The alpha-3 chain forms a triple helix with
alpha 4/5 chains, combining with another
triple helix to form a hexamer
 The antibodies DO NOT BIND the intact
hexamer, binding only when it dissociates
 In vivo studies indicate that the alpha 3
epitopes are sequestered under normal
circumstances (hidden) and become
exposed due to some disruption of the
GBM

15. Pathogenesis: Autoreactive T Cells
 T cell infiltrates typically found on biopsy
 T cell proliferative response found with
exposure to α-3 IV NC1 domain (serum from
patients with anti-GBM)
 Regulatory T cells (CD4/25+) that counter
the effects of autoreactive cells reduce the
severity of lesions in murine anti-GBM GN
 Correlation found between number of
autoreactive T cells and disease activity

16. Role of epidermal
growth factor?
constitutively expressed
in the kidney, activation
linked with RPGN
In RPGN there is an accumulation of CD4 T cells and macrophages in the tuft, proliferation of endogenous
glomerular cells, development of cellularcrescents that result from capillary damage and leakage of plasma
proteins into Bowman’s space. Crescents consist of fibrous material and proliferating
cells arising from the parietal epithelium and podocytes as well as infilatrating macrophages and fibroblasts.

17. Antigenic Triggers
 Smoking
 Exposure to hydrocarbons
 Lithotripsy
 Pulmonary Infections
 Secondary GN process
 Degradation by reactive oxygen species
Damage to the GBM revealing the epitope?
Damage to alveolar capillaries allowing
circulating antibody to interact?

18. Genetic Susceptibility
 Patients with HLA-DR15 and DR4
appear to be at increased risk
• Association with DR15 confirmed in Chinese
and Japanese studies
• Molecular analysis has revealed a particular 6
amino acid motif common to both that may
confer susceptibility
 DR1 and DR7 appear to be at lesser
risk

19. Diagnosis
 Pulmonary hemorrhage can be seen
with other acute nephritides
• SLE, ANCA+ vasculitis, patients with
pulmonary edema
 Diagnosis requires demonstration of
anti-GBM antibodies in serum or kidney
 Renal biopsy should be done unless
there is a contraindication

20. Renal Biopsy
 Light microscopy typically shows crescentic
glomerulonephritis
 Immunofluorescence demonstrates
pathognomonic findings of linear IgG
deposition along the capillaries and
occasionally distal tubules (occasionally IgA or
IgM)
 Linear IgG staining can be seen in 2 other
disorders:
• Diabetic Nephropathy
• Fibrillary Glomerulonephritis
**staining typically not as strong as with anti-GBM

21. Pathology
Findings

22. FIGURE 32-21 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

23. 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

24. Serologic Testing
 Indirect Immunofluorescence
• Requires an experienced renal pathologist
• Fluorescein-labeled anti-human IgG added to
incubation of the patient’s serum with normal renal
tissue
 ELISA serum assay for anti-GBM antibodies
• Specificity can be confirmed by Western blot
• Sensitivity varies by kit (63% to almost 100%)
• False negatives in Alport syndrome patients

25. Antineutrophil Cytoplasm
Antibodies
 Should be tested in any patient with acute GN with
or without pulmonary findings
• 10-38% of patients with anti-GBM also ANCA+ (usually
MPO)
 Low levels of ANCA may be detectable years before
production of anti-GBM antibody and onset of
symptoms
 Clinically relevant because patients with ANCA may
have more treatable disease than anti-GBM + only
• Tailor long-term management to vasculitis treatment
• These patients may have relapses of systemic vasculitis

26. Retrospective military analysis of 30 patients who
ultimately developed anti-GBM disease:
Looked back 30 years at stored serum samples obtained at the time
of enlistment and every other year after
Patients diagnosed with anti-GBM and healthy controls were identified
from the military database
Compared with matched controls, a greater number of patients with
anti-GBM disease had PR3-ANCA and MPO-ANCA levels detected in
multiple serum samples obtained in the years prior to clinical disease
82% versus 14% control for PR3-ANCA
72% versus 27% control for MPO-ANCA
In all cases, ANCA were detected in earlier samples than anti-GBM
antibodies that were detected months prior to onset of symptoms (but
not years).
Mechanism of ANCA in disease pathogenesis not clear.
Olson, et al. J Am Soc Nephrol, 2011.

27. Treatment
 Plasmapheresis + Prednisone
+ Cyclophosphamide
• Plasmapheresis removes
circulating anti-GBM
antibodies and complement
• Immunosuppression
minimizes new antibody
formation
 40-45% will benefit by not
progressing to ESRD or death
when treated with this
combination
• Recovery more likely in non-
oliguric patients
• Patients on dialysis or with
100% crescents on renal
biopsy unlikely to respond to
treatment

28. To pherese or not to pherese?
 1 randomized trial evaluated outcomes among 17 patients
prednisone and cyclophosphamide alone or with plasmapheresis
• 2/8 patients with plasmapheresis progressed to ESRD compared
with 6/9 in the immunosuppression group
• % crescents on initial renal biopsy and entry plasma creatinine
correlated better with outcomes
• Patients with creatinine <3 and <30% crescents did well
• Creatinine >4 and severe crescentic involvement did not
 Typically recommended based on 2 factors:
• improved morbidity and mortality in the era of plasmapheresis
when compared to historic rates
• The “common sense” argument of greater reduction of disease
consequences with rapid removal of anti-GBM antibody
Johnson, et al. Medicine, 1985.

29. Plasmapheresis
 Typically daily or alternate day 4-liter exchanges for 2-3 weeks
 Albumin given as replacement fluid
 1-2 units of FFP at the end of the procedure should be
substituted for albumin if recent hemorrhage or biopsy to
reverse depletion of coagulation factors by pheresis
 Monitor for metabolic alkalosis with FFP administration
 Recheck antibody titers after regimen, may need to continue
for another 2-3 weeks

30. Immunosuppressants
 Methylprednisolone 15-30 mg/kg to
a max of 1000 mg IV for 3 doses
• Followed by daily oral prednisone (max
60-80 mg per day)
 Oral cyclophosphamide 2 mg/kg per
day initial dosing
• Not to exceed 100 mg/day in those
patients > 60 years due to toxicity

31. Treatment Duration
 Optimal timing unknown, may take 6-9 months
for cessation of antibody formation
 Maintenance therapy with prednsione and
azathioprine typically given after remission
induced
• Some use 3 months of prednisone and
cyclophosphamide therapy if titers negative
• Anti-GBM antibody levels should be monitored every 1-2
weeks
 Patients presenting with dialysis-dependant renal
failure  must weigh risks of treatment

32. Treatment: Patient Selection
 Retrospective review of 71
Plasma Patient Renal
patients treated with the Creatinine Survival Survival
typical triad @ 1 year @ 1 year
 Among 42 patients with
<5.7mg/dL
100% 95%
pulmonary hemorrhage,
bleeding resolved in 90%
>5.7mg/dL
No urgent
83% 82%
Dialysis
 All patients with crescents Requiring
urgent 65% 8%
in all glomeruli on biopsy
dialysis
required long-term dialysis
Levy, et al. Ann Intern Med, 2001

33. Treatment: Patient Selection
 Recommendations are to treat with pheresis +
immunosuppression in the following situations:
• Pulmonary hemorrhage, regardless of renal involvement
• Patients with renal involvement NOT requiring
immediate RRT
• Most patients with less severe disease (30-50%
crescents) although they may do well with
methylprednisolone followed by oral prednisone
**Some consider a short trial of combination therapy in
patients with very acute disease, younger patients,
patients with ANCA+ and clinical signs of vasculitis
(purpura, arthralgias) as they may recover function.
Levy, et al. Ann Intern Med, 2001

34. Complications of Therapy
 Infection
• May be exacerbated by plasmapheresis and require IVIG
infusion
• High dose steroids  multiple adverse effects
 Cyclophosphamide-related
• Increased risk of PJP
• Amenorrhea
• Bladder toxicity (cystitis, bladder CA)

35. Novel Therapy
 Suppression of T Cell involvement via blockade of
CD28-B7 (co-stimlatory pathyway for T cell
activation)
• Fusion protein CTLA41g evaluated in rat model of anti-
GBM
• Development of crescentic GN completely prevented
• No human studies done yet

36. Prognosis
 In general, patients who survive the first year with
intact renal function do well
 Survival (patient and renal) closely correlates with
degree of renal impairment at diagnosis
 Few requiring immediate dialysis recover renal
function
 Relapses uncommon  2% in a single center study,
clinically more common with ANCA+ patients
 Higher rate of recurrence in smokers

37. Post-Transplantation Disease
 Occurs in 5-10% of renal transplants in patients with
underlying hereditary nephritis (Alport Syndrome)
 Commonly have abnormality in the alpha-5 type IV
collagen chain
• May also have alpha-3 or alpha-4 mutation
• Defective organization of alpha 3,4,5 chains in the GBM
leads to altered Goodpasture antigen in the alpha 3 chain
• Altered antigen not recognized by the GBM antibody
• Donor kidney has normal antigen, which elicits an immune
response against the “new” antigen in the transplanted
kidney
• Alloantibody produced recognizes a different epitope than
the autoantibody in Goodpasture’s disease

38. References:
 Levy JB, Turner AN, Rees AJ, et al. Long term outcome of
anti-glomerular basement membrane antibody disease
treated with plasma exchange and immunosuppressants.
Ann Intern Med. 2001;134(11):1033.
 Taal: Brenner and Rector’s The Kidney, 9th Ed. Chapter 32:
Secondary Glomerular Diseases. 2012:1224-1226
 www.unckidneycenter.org
 www.uptodate.com
*Pathogenesis and diagnosis of anti-GBM antibody
(Goodpasture’s) disease
*Treatment of anti-GBM antibody (Goodpasture’s) disease