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:
ATAGC TSI Significance of the total i-score Michael Mengel Alberta Transplant Applied Genomics Centre University of Alberta, Edmonton, Canada
10%25%0% The Banff-Consensus Lorraine Racusen & Kim Solez
Cellular rejection B Granzyme B
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 inflamed i2 - 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.
Infiltrates in areas of fibrosis and tubular atrophy
How do people score? (Poll at the 2007 Banff meeting) (0.1 - 6 mm)
Infiltrate type p 0.05 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? normalfibrosis fibrosis+ i=1 fibrosis+ i >1 p<0.001 Cosio FG et al AJT, 5:2464, 2005
Relationship of total i-score to other Banff lesions Sis B. 2009 AJT, in press
Relationship of total i-score to other Banff lesions
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
Gene sets (Spearman correlation, p<0.001) Banff-i-scoret-scoretotal-i-score T-cell associated0.5340.4840.741 γ -Interferon induced0.5320.4410.703 Kidney parenchyma associated-0.296-0.303-0.536 Injury and repair associated0.3790.3550.645 B-cell associated0.2810.2790.660 correlations between gene expression and Banff scores
Correlation with PBTs is independent of time post transplant Biopsies taken ≤6 months post Tx i-score t-scoretotal i-score T cell associated transcripts0.6330.6080.726 gamma-interferon inducible transcripts0.5870.4930.68 Kidney parenchymal transcripts-0.217-0.185-0.322 Injury inducible transcripts0.023-0.0180.191 Immunoglobulin transcripts0.2590.360.276 B-cell associated transcripts0.3360.4280.516 Biopsies taken ≤1 year post Tx i-scoret-scoretotal i-score T cell associated transcripts0.6990.6350.771 gamma-interferon inducible transcripts0.6520.5290.719 Kidney parenchymal transcripts-0.323-0.240-0.383 Injury inducible transcripts0.066-0.0480.207 Immunoglobulin transcripts0.4370.4950.457 B-cell associated transcripts0.4750.5010.611
Defining a molecular threshold for pathological inflammation
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
*p<0.05 t0-cases with high total inflammatory burden have also significantly higher other Banff scores
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
all allografts (n=104) p=0.058 A i-score <25% i-score >25% B total 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-score total i-score Banff i- and total i-score and allograft survival
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
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