Download - Significance of the total i -score
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ATAGC TSI
Significance of the total i-score
Michael MengelAlberta Transplant Applied Genomics Centre
University of Alberta, Edmonton, Canada
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ATAGC TSI
10% 25%0%
The Banff-ConsensusLorraine Racusen & Kim Solez
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ATAGC TSI
Cellular rejection
Granzyme B
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ATAGC TSI
Do not consider for i-score:- subcapsular infiltrates- perivascular infiltrates- fibrotic areas- areas of tubular atrophy
?nodular infiltrates
Do not consider for t-score:- moderately to severe atrophic tubules
?mild atrophic tubules in areas of tubular atrophy and fibrosis
?tubules in areas with minor inflammation
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 inflamedi2 - 26 to 50% of parenchyma inflamed i3 - >50% of parenchyma inflamed
Table 2 - Quantitative Criteria for Tubulitis ("t") Score (applies to tubules no more than mildly atrophic)
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.
Banff i- and t-score
Racusen L. et al., Kidney Int. 1999 Feb;55(2):713-23.
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ATAGC TSI
subcapsular perivascular
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ATAGC TSI
Infiltrates in areas of fibrosis and tubular atrophy
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ATAGC TSI
nodular Infiltrates
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ATAGC TSI
How do people score?(Poll at the 2007 Banff meeting)
Inflammation in IF/TA
24
16 17
10
0
5
10
15
20
25
30
ignore consider depends scoring changed
nodular infiltrates
17
22
17
7
0
5
10
15
20
25
ignore consider depends scoring changed
perivascular infiltrates
26
1714
3
0
5
10
15
20
25
30
ignore consider depends scoring changed
subcapsular Infiltrates
44
310
3 1.505
101520253035404550
ignore consider depends scoring changed
averagedistance in
mm
(0.1 - 6 mm)
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ATAGC TSI
0102030405060708090
100
%
protocol bx
indication bx
Infiltrate type
p 0.05
Mengel et al. Am J Transplant. 2007 Feb;7(2):356-65.
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ATAGC TSI
Infiltrates and allograft function
p 0.05
Mengel et al. Am J Transplant. 2007 Feb;7(2):356-65.
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ATAGC TSI
Infiltrates and outcome
Mengel et al. Am J Transplant. 2007 Feb;7(2):356-65.
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ATAGC TSI
A relationship between inflammation and
progression of IF/TA?
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ATAGC TSI
Inflammation as risk factor for progression of IFTA
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ATAGC TSI
Progression of ci-score and Inflammation
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ATAGC TSI
How much graft inflammation is significant?
Months post-transplant
6048362412
Gra
ft S
urvi
val
1.0
.9
.8
.7
.6
.5
.4
.3
normal
fibrosis
fibrosis+ i=1
fibrosis+ i >1
p<0.001
Cosio FG et al AJT, 5:2464, 2005
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ATAGC TSI
Scoring inflammation in renal allograft biopsies
60% IFTA compartment40% non-scarred compartment
100% Cortex
relative scoringaccording to current Banff
rules
25% = Banff i-score 1 “67% i-IFTA”
5% 3% 3% 5%
absolute scoring40% i-IFTA10% i-Banff
nodularperivascular
subc
apsu
lar
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ATAGC TSI
Infiltrates and time in BFC
0
5
10
15
20
25
30
<6 months post TX, n=42 >6 months post TX, n=87
mea
n %
cor
tex
invo
lved
nodular
perivascular
i-Banff
i-IFTA
IFTA
p<0.0001
p<0.0001
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ATAGC TSI
Relationship of total i-score to other Banff lesions
v g
ptc
cgmm
ah
cv
cict
i
t
vPRA I
PRA IIptc
cgmm
ah
cict
ptcml
i
t
Time post-transplantg
cvC4d
ti
ti
Sis B. 2009 AJT, in press
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ATAGC TSI
Relationship of total i-score to other Banff lesions
v g
ptc
cgmm
ah
cv
cict
i
t
vPRA I
PRA IIptc
cgmm
ah
cict
ptcml
i
t
Time post-transplantg
cvC4d
ti
ti
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ATAGC TSI
i-score total i-score
% c
orte
x w
ith in
filtra
te
*p<0.05
*
*
*
*
*
*
Banff i- and total i-score and diagnosis: interstitial infiltrates are not disease specific
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ATAGC TSI
Gene sets (Spearman correlation, p<0.001) 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
correlations between gene expression and Banff scores
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ATAGC TSI
Correlation with PBTs is independent of time post transplant
Biopsies taken ≤6 months post Tx i-score t-score total i-score
T cell associated transcripts 0.633 0.608 0.726gamma-interferon inducible transcripts 0.587 0.493 0.68Kidney parenchymal transcripts -0.217 -0.185 -0.322Injury inducible transcripts 0.023 -0.018 0.191Immunoglobulin transcripts 0.259 0.36 0.276B-cell associated transcripts 0.336 0.428 0.516
Biopsies taken ≤1 year post Txi-score t-score total i-score
T cell associated transcripts 0.699 0.635 0.771gamma-interferon inducible transcripts 0.652 0.529 0.719Kidney parenchymal transcripts -0.323 -0.240 -0.383Injury inducible transcripts 0.066 -0.048 0.207Immunoglobulin transcripts 0.437 0.495 0.457B-cell associated transcripts 0.475 0.501 0.611
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ATAGC TSI
Defining a molecular threshold for pathological inflammation
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ATAGC TSI
A B
C D
AUCtotal i-score 0.85i-score 0.73
p=0.012
AUCtotal i-score 0.82i-score 0.58
p=0.001
AUCtotal i-score 0.86i-score 0.86
p=0.9
AUCtotal i-score 0.97i-score 0.91
p=0.7
The total i-score is superior in reflecting the molecular inflammatory burden
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ATAGC TSI
*p<0.05
t0-cases with high total inflammatory burden have also significantly higher other Banff scores
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ATAGC TSI
ABMR
TG TCMR,GN
Borderline
CNIT
ATNOther
IFTA NOS
total i-scoreAUC = 0.81
i-scoreAUC = 0.65
← increasing ti/i-scores
total vs. i-scorep=0.012
Prognostic value of Banff i- and total i-score versus diagnosis
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ATAGC TSIall allografts (n=104)
p=0.058
A
i-score <25%
i-score >25%
Btotal i-score <25%
total i-score >25%
p<0.0001
allografts with ≥IFTA grade I (n=88)
C
D
i-score <25%
i-score >25%
p=0.599
p=0.002
total i-score <25%
total i-score >25%
i-sco
reto
tal i
-sco
reBanff i- and total i-score and allograft survival
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ATAGC TSI
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
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ATAGC TSI
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
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ATAGC TSI
Kara Allanach
Dina Badr
Sakarn Bunnag
Patricia Campbell
Jessica Chang
Gunilla Einecke
Konrad Famulski
Luis Hidalgo
Anna Hutton
Zija Jacaj
Deborah James
Bruce Kaplan
Bert Kasiske
Stromedix, AstellasRoche Molecular Systems, Roche Canada
Alberta Health ServicesUniversity Hospital Foundation
Roche Organ Transplant Research FoundationGenome Canada/Genome Alberta
University of AlbertaAlberta Ministry of Advanced Education and Technology
Canada Foundation for InnovationCanadian Institutes of Health Research
Kidney Foundation of CanadaAlberta Heritage Foundation for Medical Research
Muttart Chair in Clinical Immunology, Canada Research Chair in Life Sciences
Special thanks to our clinical collaborators
Special thanks to our patients
AcknowledgementsNathalie Kayser
Daniel Kayser
Daniel Kim
Rob Leduc
Arthur Matas
Vido Ramassar
Jeff Reeve
Gui Renesto
Joana Sellares
Banu Sis
Lin-Fu Zhu