Yeni Banff Klasifikasyonunun Getirdikleri Banu Sis, MD, FRCPC Dept of Laboratory Medicine and Pathology Alberta Transplant Applied Genomics Centre University of Alberta, Edmonton, AB, Canada 3. Ulusal Transplantasyon Immunolojisi ve Genetigi Kongresi 23 Nisan 2011
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Sunu1 [Uyumluluk Modu] A/23... · Problems with ISHLT 2004 diagnostic criteria for ABMR •A full day session was devoted to revisit criteria for ABMR in heart allografts in partnership
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Yeni Banff Klasifikasyonunun Getirdikleri
Banu Sis, MD, FRCPC
Dept of Laboratory Medicine and Pathology
Alberta Transplant Applied Genomics Centre
University of Alberta,
Edmonton, AB, Canada
3. Ulusal Transplantasyon Immunolojisi ve Genetigi Kongresi
• A full day session was devoted to revisit criteria for ABMR in heart allografts in partnership with the
ISHLT
• Problems with the current ISHLT criteria for ABMR:– Lack standardization of definitions and grading for C4d and histologic features
– Require “acute graft dysfunction” for diagnosis– Depend on screening by histology
Revisited criteria for acute ABMR in heart
allografts
Consensus was achieved on:
1. Recommending multiple time points to test for DSA2. Performing C4d staining (IF or IHC) on all cardiac allograft biopsies
3. Interpreting C4d staining only in myocardial capillaries
4. Scoring C4d staining as diffuse (>50%), focal (<50%) or negative
5. Only diffuse C4d is accepted as positive
Revisited ABMR criteria in pancreas
allografts
• Perform C4d staining in all pancreas allograft biopsies
• Remove requirement for “graft dysfunction” for the diagnosis of acute ABMR
Acute antibody mediated rejection
1.C4d+
2.Morphologic evidence of tissue injury (interacinar capillaritis, acinar cell
damage, arteritis, etc).
3.DSA testing
Two of 3 criteria necessary for diagnosis
C4d and graft pathology
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
cg mm g ptc cv PTCBMML C4d Anti-HLA
Ab
% of biopsies with TG
C4d staining
Diffuse positive
Focal positive
Negative
Histologic lesions
and PTCBMML
Severe
Moderate
Mild
Negative
Anti-HLA antibodies
Positive
Negative
Many (50%) Transplant Glomerulopathy cases with Alloantibody
are C4d negative
70% HLA antibodies
36% C4d deposition
91% PTC basement membrane multilayering
35% glomerulitis
70% peritubular capillaritis
Sis et al. AJT 2007; 7: 1743
Gloor et al. AJT 2007; 7: 2124
Miura et al. Clin Transplant 2007; 21: 8
Shimizu et al. Clin Transplant 2009; 23: 39
Early EM findings of TG in longitudinal
analysis of protocol biopsies
cg
Nankivell AJT 2007
Pre-transplant DSA & TG
Cumulative Incidence of TXG
P=0.02
Nankivell Banff 2009
DSA & PTC & glomerular C4d deposition
N =415 biopsies
Biopsies < 1 month are for cause = 98
%%
Nankivell Banff 2009
Role of endothelium in ABMR
Training set
n=81
Validation set
n=82
Incidence of transplant glomerulopathy (*%
)
No Ab
n=30
Ab with no E
n=21
Ab with E
n=30
No Ab
n=31
Ab with no E
n=31
Ab with E
n=20
C4d+ Transplant Glomerulopathy
C4d Negative Transplant Glomerulopathy
0
10
20
30
40
50
60
0
10
20
30
40
50
60
6.7%
19%
43%
6.5%
23%
60%
C4d is negative in 60% of chronic active ABMR biopsies
(=TG with Ab+ E+)
Sis et al. AJT 2009;9:2312-23
60%
C4d negative
Patients with antibody and high ENDAT expression show poor graft survival
Sis et al. AJT 2009;9:2312-23
Training set
N=81
Validation set
N=82
Phenotyping Late Kidney Transplant Loss
What Causes Late Allograft Loss?
• 1,317 kidneys, f/u of ~50 months
• 330 graft losses (25%)
– 138 death with function (41.8%)
– 39 primary nonfunction (11.1%)
– 153 death censored graft loss (46.1%)
• Glomerular: Tg, recurrence, non-
recurrence
• IF/TA—91% with diagnosis (PVN,
Immune mediated, PN, etc)
Am Journal Transplant 2009; 9:527
.
15% death censored graft losses
98% of graft losses attributable to specific causes
Glomerular disease 36%
20% recurrent disease
Most are NOT idiopathic IFTA or CNI toxicity
b) Banff diagnosis and outcome
a) Diagnosis of failed grafts by Banff classification
Survival reflect C4d+ABMR, C4d-veABMR, and GN
Time post Bx1400120010008006004002000
Cum Survival
1.0
0.8
0.6
0.4
0.2
0.0 Other
Glomerulonephritis
T cell mediated rejection or
borderline T cell mediated rejection
C4d+ Antibody mediated rejection
C4d+ Antibody mediated rejection
T cell mediated rejection
or borderline TCMR
Interstitial fibrosis and
tubular atrophy, not
otherwise specified
Other
Glomerulonephritis
p = 0.07
}
6
7
7
61
d) Antibody-associated microcirculation injury and outcome
c) Diagnosis of failed grafts in relationship to antibody
and microcirculation changes
C4d+ Antibody mediated rejection
C4d- Antibody mediated rejection
(PRA+ with microcirculation changes)
PRA-
Glomerulonephritis
PRA+ alone
(without microcirculation changes)
PRA not available
1400120010008006004002000
1.0
0.8
0.6
0.4
0.2
0.0 Glomerulonephritis
No PRA or PRA+ without microcirculation change
C4d+ Antibody mediated rejection
C4d- Antibody mediated rejection
(PRA+ with microcirculation change)
p = 0.01Cum Survival
Time post Bx
p = 0.01
6 7
10
2
1
1
Figure 1A.
a Others (n=6): C4d deposition with no pathology (n=4); Thrombotic microangiopathy (n=1); Inadequate (n=1)b Others (n=4): C4d deposition with no pathology (n=1); T. glomerulopathy (n=1) ; Thrombotic microangiopathy (n=2); Suspicious viral (n=1) c Others (n=2): Obstruction (n=1); Suspicious viral (n=1) d Others (n=9): T. glomerulopathy (n=3) ; Suspicious viral (n=2); Post-transplant lymphoproliferative disorder (n=1); IFTANOS with acute tubular necrosis
(n=1); Acute pyelonephritis (n=1); Inadequate (n=1)e Non-adherence is defined by notes in the records around the time of the biopsy. Patients with multiple biopsies are assigned to the column reflecting their
first recorded non-adherence.
IFTANOS, interstitial fibrosis and tubular atrophy not otherwise specified
Banff Working Groupsestablished in Banff 2009 Meeting
BWGs aim at addressing unmet needs within the Banff Classification to support/refute
potential changes to the classification via conducting multi-center trials.
http://cybernephrology.ualberta.ca/Banff/
Clinical significance of isolated vasculitis:
A multicenter observational study
B Sis, B Lategan, S Bagnasco, M Haas, A Magil, L Cornell, A Herzenberg, I
Gibson, P Randhawa, Y Ozluk, P Halloran, F Cosio, E Kraus
ATC 2011, oral presentation, abstract # 2203
Background
• Microarray analysis of kidney transplant biopsies with TCMR defined by Banff and transcript sets
representing:
– Cytotoxic T lymphocyte activation and infiltration– Interferon gamma-effects– Parenchymal deterioration
• Several outliers for this correlation
Intimal arteritis without significant
tubulo-interstitial inflammation
Microarray study of 143 consecutive kidney transplant biopsies identified
isolated v cases with low inflammatory gene set scores
Mueller et al.
AJT 7:2712-2722, 2007
Isolated v lesion
A biopsy from U of Manitoba
Pictures by Ian Gibson
v3, all other acute Banff scores 0, C4d 0
DSA class II+, graft function N
“isolated v” Lesion
Does this represent a
true acute rejection?
Study question
Study aims
• To determine the clinical significance of isolated v lesion in kidney transplant biopsies
– In terms of graft function –Graft survival
• To determine whether we need to refine Banff criteria to call TCMR based on vasculitis alone
(Banff II/III)
Isolated v-lesion BWG
• To address the clinical significance of isolated v- lesions (with little or no
tubulo-interstitial inflammation) in renal allograft biopsies.
• To determine whether we need to refine Banff criteria to call TCMR Banff
II/III
• N=300 biopsies
• GROUP 1= Isolated v lesion
– v>0 and t<2 and i <2 and C4d-
• GROUP 2= Vasculitis + IA/IB
– v>0 and i>1 and t>1 and C4d-
• GROUP 3= No vasculitis
– v0 and t<2 and i<2 and C4d-
0
5
10
15
20
25
30
35
40
45
Clinical data at biopsy
Group 1 Group 2 Group 3 P-value P-value
Isolated v1 v1 and tubulointerstitial
rejection
v0 and minor
tubulointerstitial
inflammation
Group
1 vs. 2
Group
1 vs. 3
N 117 48 45
Indication for biopsy
Rising creatinine 41 14 12 NS NS
DGF 27 0 0 0.000274 0.000416
Clinical, other 41 33 25 NS 0.017356
Protocol 8 1 8 NS 0.046
Serum Creat at biopsy 4.2 ± 2.9 3.0 ± 1.9 4.4 ± 3.1 0.015 NS
Time post transplant at
biopsy, median
17 33 12 NS NS
Time at biopsy, <6 mo 91 39 39 NS NS
Future function
Group 1 Group 2 Group 3 P-value P-value
Isolated v1 v1 and
tubulointerstitial
rejection
v0 and minor
tubulointerstitial
inflammation
Group
1 vs. 2
Group
1 vs. 3
N
sCreat at 1 mo 2.2 ± 1.6 2.1 ± 0.9 2.3 ± 1.4 NS NS
sCreat at 6 mo 2.0 ± 1.5 1.9 ± 0.8 2.3 ± 1.8 NS NS
Patient, deceased 17/100 pts
(8 unknown)
5/43 pts
(3 unknown)0/45 pts
Death censored
graft failure
20/104 pts
(4 unknown)6/46 pts 7/45 pts
Graft survival
Isolated v1 (v1 and i<1 and t<2)
v1 and i>1 and t>1
v0 and i<2 and t<2
p=0.289
conclusions
• Isolated v1 biopsies are seen early and associated with a high incidence of delayed graft function;
• v1 with or without high tubulointerstitial inflammation is not related to increased graft failure compared to v0.
• Thus, isolated v1 lesions, after the exclusion of antibody-mediated rejection, are of two types: T cell-mediated rejection
and injury, and have no independent prognostic significance.
Antibody-mediated vasculitis
Banff criteria need to be revisited
• Current Banff – only v3 in the presence of DSA and C4d
• However, alloantibody may mediate milder forms of vasculitis intimal arteritis (Edmonton and Paris data)
• Presence of v1/v2 should should not be interpreted as supporting the diagnosis of TCMR unless other features are
present
• DSA testing crucial (C4d is often negative).
Milder forms of intimal arteritis is often associated with
DSA
0
10
20
30
40
50
60
70
80
90
100
v 0 v>0
56%44%
DSA (-)
DSA (+)
0
10
20
30
40
50
60
70
80
90
100
v 0 v>0
C4d negative
C4d focal or diffuse
33%67%
% of biopsies
n=172 n=27 n=189 n=27
p=0.017 p=0.023
Sis et al AJT 2010; 10:421-30
PVN staging BWG
• Volker Nickeleit proposed a classification of PVN includes 3 stages, approved by consensus
• stage-A (early changes, without tubular epithelial
cell necrosis);
• stage-B (active nephropathy with virally induced tubular necrosis);
• stage C (late sclerosing changes)
• Pending for reproducibility studies
Molecular Pathology BWG
• Led by Phil Halloran will facilitate the consensus about how and which molecular markers can be integrated into the Banff
classification.
• RT-PCR or chip (with few genes) based molecular measurements may be incorporated into the existing
histology-based Banff classification
• Discovery of new diagnostic and/or prognostic tissue markers could be feasible with the help of omics technologies.
Other BWGs
• Fibrosis scoring BWG:
• Aim: To standardize fibrosis scoring in renal native and allograft biopsies,
and conduct multi-center reproducibility trials to improve interobserver
agreement.
• Glomerular lesion scoring BWG:
• Aim: To re-examine scoring glomerular double contours (cg), glomerulitis
(g), and mesangial matrix increase (mm) aiming at refinement of these
criteria to increase the interobserver reproducibility.
• Quality assurance BWG:
• Aim: To plan Banff training courses, proficiency tests, and
immunohistochemistry (C4d and BK) multicentre staining trials.
•
Glomerular lesion scoring trial
– in progress
• 23 pathologists participated from 10 countries
• Online virtual microscopy assessment of biopsies– reproducibility studies
– Correlation with clinical outcomes
• Management of sensitized patients• A new concept of C4d negative ABMR• Reports from Banff Working Groups –Significance of isolated vasculitis (Sis et al)–Glomerular Lesion Scoring (Sis et al)–Fibrosis scoring (Colvin et al)–Polyoma virus nephropathy staging (Nickeleit et al)–Quality assurance in transplant pathology (Mengel et al)
• Role of epithelium in allograft deterioration• Molecular Pathology in Transplantation• New insights from Protocol Biopsies
2011 Banff meeting, June 6-10
Paris, France
THANK YOU…
See you in the next Banff Conference in Paris (6-10 June 2011)