Transcript Slide 1

Significance of the total i-score
Michael Mengel
Alberta Transplant Applied Genomics Centre
University of Alberta, Edmonton, Canada
ATAGC TSI
The Banff-Consensus
Lorraine Racusen & Kim Solez
0%
10%
25%
Cellular rejection
Granzyme B
Banff i- and t-score
Table 4 - Quantitative Criteria for
Mononuclear Cell Interstitial Inflammation
("i") Scores
i0 - No or trivial interstitial inflammation
(<10% of unscarred parenchyma)
i1 - 10 to 25% of parenchyma inflamed
i2 - 26 to 50% of parenchyma inflamed
i3 - >50% of parenchyma inflamed
Do not consider for i-score:
-subcapsular infiltrates
-perivascular infiltrates
-fibrotic areas
-areas of tubular atrophy
?nodular infiltrates
Table 2 - Quantitative Criteria for Tubulitis
("t") Score (applies to tubules no more than mildly atrophic)
Do not consider for t-score:
t0 - No mononuclear cells in tubules
t1 - Foci with 1 to 4 cells/tubular cross section or
10 tubular cells
t2 - Foci with 5 to 10 cells/tubular cross section
t3 - Foci with >10 cells/tubular cross section, or
the presence of at least two areas of tubular
basement membrane destruction
accompanied by i2/i3 inflammation and t2
tubulitis elsewhere in the biopsy.
?mild atrophic tubules in areas of tubular
atrophy and fibrosis
-moderately to severe atrophic tubules
?tubules in areas with minor inflammation
Racusen L. et al., Kidney Int. 1999 Feb;55(2):713-23.
subcapsular
perivascular
Infiltrates in areas of fibrosis and tubular atrophy
nodular Infiltrates
How do people score?
(Poll at the 2007 Banff meeting)
nodular infiltrates
Inflammation in IF/TA
30
25
22
24
25
20
20
16
17
15
17
17
15
10
10
10
7
5
5
0
0
ignore
consider
depends
scoring changed
ignore
perivascular infiltrates
30
25
17
14
15
10
3
5
50
45
40
35
30
25
20
15
10
5
0
consider
depends
scoring changed
44
10
3
ignore
0
ignore
depends
subcapsular Infiltrates
26
20
consider
scoring changed
consider
3
depends
scoring
changed
1.5 (0.1 - 6 mm)
average
distance in
mm
Infiltrate type
100
90
80
70
%
60
50
40
p  0.05
protocol bx
indication bx
30
20
10
0
Mengel et al. Am J Transplant. 2007 Feb;7(2):356-65.
Infiltrates and allograft function
p  0.05
Mengel et al. Am J Transplant. 2007 Feb;7(2):356-65.
Infiltrates and outcome
Mengel et al. Am J Transplant. 2007 Feb;7(2):356-65.
A relationship between
inflammation and
progression of IF/TA?
Inflammation as risk factor for progression of
IFTA
Progression of ci-score and
Inflammation
How much graft inflammation is significant?
1.0
normal
.9
fibrosis
.8
.7
fibrosis+ i=1
.6
fibrosis+ i >1
.5
.4
p<0.001
.3
12
24
Cosio FG et al AJT, 5:2464, 2005
36
Months post-transplant
48
60
Scoring inflammation in renal allograft biopsies
100% Cortex
nodular
perivascular
subcapsular
10% i-Banff
5%
3%
25% = Banff i-score 1
40% non-scarred
compartment
3%
40% i-IFTA
absolute scoring
“67% i-IFTA”
relative scoring
5%
60% IFTA compartment
according to
current Banff
rules
Infiltrates and time in BFC
30
p<0.0001
mean % cortex involved
25
p<0.0001
20
nodular
perivascular
15
i-Banff
i-IFTA
IFTA
10
5
0
<6 months post TX, n=42
>6 months post TX, n=87
Relationship of total i-score to other Banff lesions
ah
cg
mm
cv
g
v
ptc
ci
ct
i
t
ti
ah
cg
C4d
v
ptc
g
PRA II
PRA I
mm
ptcml
Time
post-transplant
cv
ci
Sis B. 2009 AJT, in press
Relationship of total i-score to other Banff lesions
ah
cg
mm
cv
g
v
ptc
ci
ct
i
t
ti
ah
cg
C4d
v
ptc
g
PRA II
PRA I
mm
ptcml
cv
ci
ct
i
t
ti
Time
post-transplant
Banff i- and total i-score and diagnosis: interstitial infiltrates are not
disease specific
*
total i-score
i-score
*p<0.05
*
% cortex with infiltrate
*
*
*
*
correlations between gene expression and
Banff scores
Gene sets
Banff-i-score
t-score
total-i-score
T-cell associated
0.534
0.484
0.741
γ-Interferon induced
0.532
0.441
0.703
Kidney parenchyma associated
-0.296
-0.303
-0.536
Injury and repair associated
0.379
0.355
0.645
B-cell associated
0.281
0.279
0.660
(Spearman correlation, p<0.001)
Correlation with PBTs is independent of
time post transplant
Biopsies taken ≤6 months post Tx
T cell associated transcripts
gamma-interferon inducible transcripts
Kidney parenchymal transcripts
Injury inducible transcripts
Immunoglobulin transcripts
B-cell associated transcripts
i-score
0.633
0.587
-0.217
0.023
0.259
0.336
t-score
0.608
0.493
-0.185
-0.018
0.36
0.428
total i-score
0.726
0.68
-0.322
0.191
0.276
0.516
Biopsies taken ≤1 year post Tx
T cell associated transcripts
gamma-interferon inducible transcripts
Kidney parenchymal transcripts
Injury inducible transcripts
Immunoglobulin transcripts
B-cell associated transcripts
i-score
0.699
0.652
-0.323
0.066
0.437
0.475
t-score
0.635
0.529
-0.240
-0.048
0.495
0.501
total i-score
0.771
0.719
-0.383
0.207
0.457
0.611
Defining a molecular threshold for
pathological inflammation
The total i-score is superior in reflecting the molecular
inflammatory burden
A
B
p=0.001
p=0.012
AUC
AUC
total i-score 0.85
total i-score 0.82
i-score
i-score
0.73
C
0.58
D
p=0.7
p=0.9
AUC
AUC
total i-score 0.86
total i-score 0.97
i-score
i-score
0.86
0.91
t0-cases with high total inflammatory burden have
also significantly higher other Banff scores
*p<0.05
Prognostic value of Banff i- and total i-score versus diagnosis
← increasing ti/i-scores
total i-score
AUC = 0.81
total vs. i-score
p=0.012
i-score
AUC = 0.65
ABMR
TG
TCMR,GN
Borderline
Other
IFTA NOS
CNIT
ATN
Banff i- and total i-score and allograft survival
A
C
i-score <25%
i-score <25%
i-score
i-score >25%
i-score >25%
p=0.599
p=0.058
B
D
total i-score <25%
total i-score
total i-score <25%
total i-score >25%
p<0.0001
all allografts (n=104)
total i-score >25%
p=0.002
allografts with ≥IFTA grade I (n=88)
Conclusions about new total-i-score
• Comprises primarily two major
•
•
inflammatory compartments:
– i-Banff (non-scarred)
– i-IFTA (scarred)
reflects better the molecular burden of
inflammation and tissue injury
more robust predictor of allograft survival
Proposal for total i-score
• Test reproducibility for i-Banff, i-IFTA, and
total i-score:
– if feasible, reporting of the different
inflammatory compartments might allow to
design new clinical trials
• Incorporate into the Banff-classification as
a prognostic lesion
– either as ti-score alone or together with
i-Banff and i-IFTA
Acknowledgements
Kara Allanach
Nathalie Kayser
Dina Badr
Daniel Kayser
Sakarn Bunnag
Daniel Kim
Patricia Campbell
Rob Leduc
Jessica Chang
Arthur Matas
Gunilla Einecke
Vido Ramassar
Konrad Famulski
Jeff Reeve
Luis Hidalgo
Gui Renesto
Anna Hutton
Joana Sellares
Zija Jacaj
Banu Sis
Deborah James
Lin-Fu Zhu
Stromedix, Astellas
Roche Molecular Systems, Roche Canada
Alberta Health Services
University Hospital Foundation
Roche Organ Transplant Research Foundation
Genome Canada/Genome Alberta
University of Alberta
Alberta Ministry of Advanced Education and Technology
Canada Foundation for Innovation
Canadian Institutes of Health Research
Kidney Foundation of Canada
Alberta Heritage Foundation for Medical Research
Muttart Chair in Clinical Immunology,
Canada Research Chair in Life Sciences
Bruce Kaplan
Bert Kasiske
Special thanks to our clinical collaborators
Special thanks to our patients
ATAGC TSI