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

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Presentation on theme: "ATAGC TSI Significance of the total i-score Michael Mengel Alberta Transplant Applied Genomics Centre University of Alberta, Edmonton, Canada."— Presentation transcript:

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

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

3 Cellular rejection B Granzyme B

4 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) i to 25% of parenchyma inflamed i 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 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? normalfibrosis fibrosis+ i=1 fibrosis+ i >1 p<0.001 Cosio FG et al AJT, 5:2464, 2005

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

17 Infiltrates and time in BFC 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 i-score total i-score % cortex with infiltrate *p<0.05 * * * * * * Banff i- and total i-score and diagnosis: interstitial infiltrates are not disease specific

21 Gene sets (Spearman correlation, p<0.001) Banff-i-scoret-scoretotal-i-score T-cell associated γ -Interferon induced Kidney parenchyma associated Injury and repair associated B-cell associated correlations between gene expression and Banff scores

22 Correlation with PBTs is independent of time post transplant Biopsies taken ≤6 months post Tx i-score t-scoretotal i-score T cell associated transcripts gamma-interferon inducible transcripts Kidney parenchymal transcripts Injury inducible transcripts Immunoglobulin transcripts B-cell associated transcripts Biopsies taken ≤1 year post Tx i-scoret-scoretotal i-score T cell associated transcripts gamma-interferon inducible transcripts Kidney parenchymal transcripts Injury inducible transcripts Immunoglobulin transcripts B-cell associated transcripts

23 Defining a molecular threshold for pathological inflammation

24 AB CD AUC AUC total i-score 0.85 i-score 0.73 p=0.012 AUC AUC total i-score 0.82 i-score 0.58 p=0.001 AUC AUC total i-score 0.86 i-score 0.86 p=0.9 AUC AUC total i-score 0.97 i-score 0.91 p=0.7 The total i-score is superior in reflecting the molecular inflammatory burden

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

26 ABMR TGTCMR,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 Prognostic value of Banff i- and total i-score versus diagnosis

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

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 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, 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 Acknowledgements Nathalie Kayser Daniel Kayser Daniel Kim Rob Leduc Arthur Matas Vido Ramassar Jeff Reeve Gui Renesto Joana Sellares Banu Sis Lin-Fu Zhu


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