Dr.Michael Mengel's meeting summary of kidney section of 2011 Eleventh Banff Conference on Allograft Pathology, June -10, 2011 in Paris, France.

1. Summary of organ Session and future outlook Kidney

2. Pre-meeting Symposium: The Diagnostic and Therapeutic Challenges of the Sensitized Patient Having an anti-HLA antibody is associated with an increased risk for graft failure Sensitivity and specificity of methods for detecting antibody has significantly improved but standardization is currently underway Challenge is to assign precise risk / phenotype to the individual patient, if accomplished this will allow to design powerful clinical trials: There is an obvious difference in early ABMR (type I) in the pre-sensitizedpatient versus the late ABMR with de novo antibody (Type II), not only in clinically but most likely also in mechanism Currently available drugs show some therapeutic effects (in de-sensization and treatment), but combination therapy is necessary and needs to be demonstrated in randomized trials

3. Kidney Session I: Microvascularand arterial lesions in the sensitized patient .Working Lunch: Should C4d-negative ABMR be integrated into the Banff classification? Broad recognition of C4d-negative ABMR cases! A Working group will form and develop detailed diagnostic criteria for C4d-negative ABMR Microcirculation inflammation key histological lesion for antibody-mediated graft injury with development of TG as the end-point. However, not all cases of TG are antibody-induced and not all cases with TG show active ongoing antibody-mediated injury Obviously a significant proportion of lesions in large arteries is antibody-mediated The role of NK cells in mediating the injury in the circulation needs to be elucidated

4. Progress Report Banff Working groups BIFQUIT-Trial results C4d IHC shows fair to moderate reproducibility between laboratories and observers BK IHC shows substantial inter-observer reproducibility, however the inter-laboratory reproducibility is quite limited Glomerular lesions working group Glomerulitis inter-observer reproducibility is weak: working group will continue to refine the criteria TG inter-observer reproducibility is acceptable Isolated v-lesions working group isolated v1 lesions, after the exclusion of antibody-mediated rejection, are most likely of two types: T cell-mediated rejection and injury, and have no independent prognostic significance Implantation biopsy working group Further trials are necessary comparing larger series of wedge vs. core biopsy and frozen vs. paraffin of both biopsy types Aim of implant biopsy should not be to provide rationale to discard organs. Not conclusive data support any decision to discard an organ solely based on histology in an implant biopsy Polyoma classification working group Proposed grading schema shows with the exception of a few outliers good reproducibility However, clinical relevance for discriminating stage A vs. B was questioned and probably needs more validation. Clearly stage C cases have a worse prognosis Fibrosis working group Good correlation of eye-balling fibrosis with computer/IHC based image analysis was observed, with Trichrome being superior to PAS Better anti-correlation between image analysis and GFR was found compared to eye-balling with GFR

5. Role of parenchyma in allograft deterioration Excellent debate about the existence of EMT with a clear outcome: it does not exist ! No evidence that tubular epithelial cell cross the basement membrane and produce/lay down fibrous tissue in the interstitium However, overwhelming evidence that tubular epithelial cells in situ can assume a de-differentiated, embryonal, mesenchymal phenotype as the response to injury and an attempt to repair We need a new term for this process! Epithelial mesenchymal metaplasia Epithelial de-differentiation Epithelial ……………...

6. Molecular pathology in Transplantation:Integrating molecular diagnostics into the Banff classification Significant progress has been made in kidney with further developing the molecular microscope based on more standardized methodological tools General desire of the community is to have an integrated reporting system of molecular findings as an complementary adjunct to histopathology However, yet no comprehensive data are available from other organs, but unmet needs are identified in these organs

7. Kidney-Session II: Novel insights from protocol biopsies More long-term dataarenowavailable: there is obviously a group of patients in which persistant inflammation is present, causes progressive deterioration and no specific disease process can be indentified – what are these? Interpretation of protocol biopsy findings needs to be done in the clinical context of prior disease probability and time post transplantation The significance of chronic CNI-toxicity is still debated and needs longer term observation in larger patient groups, but ultimately randomized comparison to CNI-free patients to be defined