1. Significance of the total i-score
Michael Mengel
Alberta Transplant Applied Genomics Centre
University of Alberta, Edmonton, Canada

2. Lorraine Racusen & Kim Solez
10%
25% 0%
The Banff-Consensus
Lorraine Racusen & Kim Solez

3. Cellular rejection
Granzyme B

4. 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)
i to 25% of parenchyma inflamed
i 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)
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.
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
Racusen L. et al., Kidney Int Feb;55(2):

5. subcapsular
perivascular

6. Infiltrates in areas of fibrosis and tubular atrophy

7. nodular Infiltrates

8. How do people score? (Poll at the 2007 Banff meeting)
( mm)

9. Infiltrate type
p  0.05
Mengel et al. Am J Transplant Feb;7(2):

10. Infiltrates and allograft function
p  0.05
Mengel et al. Am J Transplant Feb;7(2):

11. Infiltrates and outcome
Mengel et al. Am J Transplant Feb;7(2):

12. A relationship between inflammation and progression of IF/TA?

13. Inflammation as risk factor for progression of IFTA

14. Progression of ci-score and Inflammation

15. How much graft inflammation is significant?
normal
fibrosis
fibrosis+ i=1
fibrosis+ i >1
Reading protocol biopsies versus reading clinical biopsies. The criteria are different. In setting clinical criteria we want to treat those pathologic findings that are of clinical significance. At the same time, we do not want to over-treat with the fear that treatment maybe worse than disease.
Protocol biopsies put “teeth” under the arbitrarily decided criteria that define disease. For example, the criteria for cellular AR is based on arbitrary counts of cells in tubules.
These data suggest that any degree of inflammation is relevant.
What about the inflammation that occurs in areas of fibrosis. Clearly, this is difficult to interpret. However, as Nankivell has suggested not all fibrotic areas have inflammation so if they have, what does it mean?
p<0.001
Cosio FG et al AJT, 5:2464, 2005

16. Scoring inflammation in renal allograft biopsies
100% Cortex 5% 3%
absolute scoring
40% i-IFTA
10% i-Banff
nodular
perivascular
subcapsular
60% IFTA compartment
40% non-scarred
compartment
relative scoring
according to current Banff rules
25% = Banff i-score 1
“67% i-IFTA”

17. Infiltrates and time in BFC
p<0.0001
p<0.0001

18. Relationship of total i-score to other Banff lesions
Sis B AJT, in press

19. Relationship of total i-score to other Banff lesions

20. Banff i- and total i-score and diagnosis: interstitial infiltrates are not disease specific*
i-score
total i-score
*p<0.05 * * *
% cortex with infiltrate * *

21. correlations between gene expression and Banff scores
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

22. 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
0.726
gamma-interferon inducible transcripts
0.587
0.493
0.68
Kidney parenchymal transcripts
-0.217
-0.185
-0.322
Injury inducible transcripts
0.023
-0.018
0.191
Immunoglobulin transcripts
0.259
0.36
0.276
B-cell associated transcripts
0.336
0.428
0.516
Biopsies taken ≤1 year post Tx
i-score
t-score
total i-score
T cell associated transcripts
0.699
0.635
0.771
gamma-interferon inducible transcripts
0.652
0.529
0.719
Kidney parenchymal transcripts
-0.323
-0.240
-0.383
Injury inducible transcripts
0.066
-0.048
0.207
Immunoglobulin transcripts
0.437
0.495
0.457
B-cell associated transcripts
0.475
0.501
0.611

23. Defining a molecular threshold for pathological inflammation

24. The total i-score is superior in reflecting the molecular inflammatory burden
AUC
total i-score
i-score
p=0.012
AUC
total i-score
i-score
p=0.001 C D
AUC
total i-score
i-score
p=0.9
AUC
total i-score
i-score
p=0.7

25. t0-cases with high total inflammatory burden have also significantly higher other Banff scores
*p<0.05

26. Prognostic value of Banff i- and total i-score versus diagnosis
ABMR TG
TCMR,GN
Borderline
CNIT
ATN
Other
IFTA NOS
total i-score
AUC = 0.81
i-score
AUC = 0.65
← increasing ti/i-scores
total vs. i-score
p=0.012

27. Banff i- and total i-score and allograft survival
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% A
i-score <25%
i-score
i-score >25%
p=0.058 B
total i-score <25%
total i-score
total i-score >25%
p<0.0001
all allografts (n=104)

28. 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

29. 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

30. Acknowledgements Special thanks to our clinical collaborators
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
Nathalie Kayser
Daniel Kayser
Daniel Kim
Rob Leduc
Arthur Matas
Vido Ramassar
Jeff Reeve
Gui Renesto
Joana Sellares
Banu Sis
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
Special thanks to our clinical collaborators
Special thanks to our patients