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Significance of the total i -score

Significance of the total i -score. Michael Mengel Alberta Transplant Applied Genomics Centre University of Alberta, Edmonton, Canada. 0%. 10%. 25%. The Banff-Consensus Lorraine Racusen & Kim Solez. Cellular rejection. Granzyme B. Banff i- and t-score. Do not consider for i-score:

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Significance of the total i -score

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

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

  3. Cellular rejection Granzyme B

  4. Banff i- and t-score • Do not consider for i-score: • subcapsular infiltrates • perivascular infiltrates • fibrotic areas • areas of tubular atrophy • ?nodular infiltrates 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 t-score: • moderately to severe atrophic tubules • ?mild atrophic tubules in areas of tubular atrophy and fibrosis • ?tubules in areas with minor inflammation 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. Racusen L. et al., Kidney Int. 1999 Feb;55(2):713-23.

  5. perivascular subcapsular

  6. Infiltrates in areas of fibrosis and tubular atrophy

  7. nodular Infiltrates

  8. How do people score?(Poll at the 2007 Banff meeting) (0.1 - 6 mm)

  9. Infiltrate type p  0.05 Mengel et al. Am J Transplant. 2007 Feb;7(2):356-65.

  10. Infiltrates and allograft function p  0.05 Mengel et al. Am J Transplant. 2007 Feb;7(2):356-65.

  11. Infiltrates and outcome Mengel et al. Am J Transplant. 2007 Feb;7(2):356-65.

  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 p<0.001 Cosio FG et al AJT, 5:2464, 2005

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

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

  18. Relationship of total i-score to other Banff lesions Sis B. 2009 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 * total i-score i-score *p<0.05 * * * % cortex with infiltrate * *

  21. correlations between gene expression and Banff scores

  22. Correlation with PBTs is independent of time post transplant

  23. Defining a molecular threshold for pathological inflammation

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

  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 ← 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 CNIT Other ATN IFTA NOS

  27. Banff i- and total i-score and allograft survival A C i-score <25% i-score <25% i-score >25% i-score >25% i-score p=0.599 p=0.058 B D total i-score <25% total i-score <25% total i-score total i-score >25% total i-score >25% p<0.0001 p=0.002 all allografts (n=104) allografts with ≥IFTA grade I (n=88)

  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 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

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