1 / 27

Updates- Banff 07

Updates- Banff 07. Issues from the Banff 07 meeting. Focal vs diffuse C4d Parmjeet Randhawa. Review of definitions - % capillaries vs area

jonas-baxter
Télécharger la présentation

Updates- Banff 07

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Updates- Banff 07 Issues from the Banff 07 meeting

  2. Focal vs diffuse C4d Parmjeet Randhawa • Review of definitions - % capillaries vs area • Kayler et al, 2008 - t3 in focal, v1 in diffuse; PC  25% f=d; Elisa class I ab  in d vs neg, class II ab 83% in d, 52% in f, 32% in neg; incomplete response to steroids/higher creat/ graft loss higher in both f and d; f and d equivalent on paraffin sections- Rx if f or d • Kedianisis, 2009- focal C4d correlated with AR, g+, ptc+, cg - 68% dsAb+; f and d C4d- pathology, correlation with dsAb, graft loss similar • Recommended multi-center assessment of technical aspects of staining for C4d on paraffin- sections from different centers to be circulated for staining in different laboratories

  3. “Total Inflammation/ti” score Michael Mengel • Background of “ti”- concern that any inflammation may be bad for graft; “i” score deliberately avoided areas of eg fibrosis to achieve specificity for AR dx • Relationship - inflammation and progression of IF/TA • Relational analysis - “ti” asso with “i” and “t” • More predictive of outcome, molecular transcripts than “i” in early or late biopsies • Recommended tests of reproducibility, potential incorporation into Banff schema as prognostic factor

  4. Isolated “v” lesion Banu Sis/Ed Kraus • Molecular asso - outlier from strong T cell signals - 9 cases U of A- V+ but C4d- (3 Ab+); compared to 9 cases with v + i2/3 and t2/3- had similar INF, alternative macro activation, kidney epi transcripts; Conclusions - some iso v AMR, some TMR, some ? • JHU - iso v1 in both compat and incompat - similar timing (early); some asso with DGF/SGF - ? Ischemic in some;  in incompatible tx • Plan - multi-center study - 7 centers so far with 144 bx iso v; to determine clinical significance, readdress Banff criteria; issues for study - criteria for dx/control groups?/exclusion criteria • BREAKFAST MEETING TO DISCUSS FURTHER

  5. Alternative ah scoring (aah)V. Broeker • Ah - poor reproducibility, not well-evaluated - proposal from Mihatsch for aah- intimal vs nodular, focal vs diffuse • Aims: to assess prevalence & progression, relationship to clinical factors • Intimal& nodular ah, smooth muscle vac- stable for 2 yrs then- inter-related; f became d; in protocol bx - variable on serial bx - ? Due to focality, reversibility? • Focal lesions mild, diffuse lesions severe • No difference - no ah, ah, vac, and ah+ vac in CsA/FK trough levels at bx, BP, DM; significant asso with male gender, donor age; better function with no ah • Remains a problematic lesion

  6. Significant of 0 time bx C. Legendre • Purposes - prediction of function, survival; whether to use the organ; baseline for later bx • Review of individual features that have been correlated with outcome - GS, AS, IF/TA, ah; review of aggregate pathology indexes • Summary: 0 time bx findings lead to organ discard; path + clin/demo date better than path only; prediction of outcome- many other factors will supervene after 0 time; should be standardized; recommend scoring system- multi-center validation

  7. Classification - PPV nephropathy V. Nickeleit/Mihatsch • Drachenberg et al- noted stages of PVN, progression to more inflammation, fibrosis; bx in early phase asso with better outcome • Proposal for consensus classification system - separate early/minimal vs late/sclerosing; include typical signs of replication, use ci/ct, score “histological load” of virus, Dx concurrent processes including rejection • Draft schema - Stages A, B, C - early with no tubular injury, fibrosis; stage B with tubular injury, often inflammation; stage C with fibrosis • Adequacy criteria proposed- 2 cores, cortex and medulla • Working luncheon

  8. C4d and AMR

  9. Relationship of TG to C4d and AMR - B. Sis • TG evolves over time; pathogenesis ill-defined • Correlative study - 3.1 % of pts with cg at median 5.5 yrs; PTCBML 91% of cg but scores not correlated; C4d 35-40%, 70% HLA Ab; ptc 70%, cv 90%, g 25% • Gloor et al 2007- cg asso with anti-class II;  in XM+, ABOI • Haas et al 2007- cg  in XM+; Mira et al- in ABOI • cg +/- C4d - similar survival; cg + ENDAT- survival • Majority of cg =late AMR; technical issues with C4d staining?

  10. C4d with minimal histology M. Haas • Early in C4d- TG later; TG bad so C4d bad • ABOI vs antiHLA- more often protocol bx, no ptc margination • ABOI cohort - 21/37 C4d+ AB+ no AR; 12/37 - C4d-; 4/37 subclinical AMR - no difference in Cr (stable) • cg + ci+ ct + cv (12 mo)- 3.9 in C4d-, 2.4 in C4d+ • Dickenman et al 2006 - C4d+ no AR - with Rx creat lower, no graft loss; if C4d+ - cg only in those with subclinical AMR; a few C4d- had ptc, g3

  11. Early cg detection B. Nankivell • *SPK recipients - protocol bx 1, 3, 6 12 mos- analysis retrospective from dx of cg • changes as early as 1 mo - glom EC thickening, vac; multilayers beneath EC, LR; later - mesangium, mm • in ptc - loss of fenestrations, EC thickening, BML • early C4d+-  later ptc, glom LR, etc • lower GFR,  survival • *Retrospective - pre-tx DsAb reassessed with luminex - found 3 cohorts - dsAb+, antiHLA, HLA-; dsAb+ - Cr, GFR, early C4d+ (55% by IHC)- became 0; cg; subclinical AMR • “strong” dsAb - C4d, survival- less effect with FK/MMF

  12. Role of C4d-fixing Ab in AMR H. Regele • In vitro - aorta, adrenal EC - incubated with recipient IgG + serum as C source- genes differed in EC types • cytokines added - huge gene response in both • C fixed to cells - C3d short time, IgG, C4d persist- MAC present • Ab + serum vs serum only - no difference in genes! Maybe inflammatory cells required, maybe other effects not requiring genes

  13. Prognostic factors in AMR D. Glotz • Types of AMR- capillary vs arterial - no additional literature • MICA, HLA Ab- worse outcome - different modes of action • Delay in Dx - no literature on impact on survival • Rx - many regimens- difficult to tease out impact of single Rx modality • Lafaucher 2007, 2009- bad prognosis histology - g, ptc PMN, cap dil, edema, macro, vasculitis; persistent C4d had no impact; persistent dsAb bad- better with PPV/IVIG/Rit; MFI max 5000 -  survival • Everly 2009- reduction of dsAb by 50% to better outcome • Need better markers - more collaborative studies

  14. Does graft accomodation occur? J. Gloor • Low-level anti-HLA may confer resistance to C-mediated lysis - survival pathway • Definition - dsAb but normal function, histology • Spectrum of AMR changes - chronic =TG (EM); CD34 - ptc disappear- obliterative vasculopathy; IF/TA also seen - ischemic • Functional definition - no, need histology • No accomodation based on histology!!- cg

  15. Protocol Bx in ABO-I K. Tanabe • AAMR in ABO-I- creatinine, IF/TA, cg- need to prevent AMR • Dx criteria - problematic in ABOI- C4d non-specific, usually some Ab and titers correlate poorly with survival • ds anti-HLA ab risk factor for AMR, vascular AR, CAMR • Rx with FK+MMF+Rit+PP+ basilixamab- AMR, AVR, CAMR

  16. Controversies in Dx of AMR M. Samaniego • Dx criteria - C4d has technical issues, interpretation of minimal and focal unclear • Ab levels - some threshold level important- but interpretation complex; dsAb worse; level of DsAb at bx correlates with severity • ? What to do with subclinical AMR • ? Outcome always bad after 5 years in incompatible grafts • Many protocols to Rx late de novo Ab - what works? • Need to treat ALL with dsAb and dysfunction • TG is the dreaded outcome - therapies not good • Data analysis, standardization needed • Perhaps incompatible transplants not the answer - focus on registry of sensitized patients and paired exchange • PREVENTION OF AMR BEST

  17. CG and other glomerular lesions M. Haas • Cg - should cg1 be 1-25%? Should the number of involved gloms be the criterion- or notation of most severe with % gloms involved • Technical - must be thin sections, PAS/silver • EM needed? Recommended? Perhaps to be done after 1 year, especially in at-risk patients • Other modalities - IHC for C4d; C5b-9 positive in loops; other?- endothelial activation • Multi-center study - g, cg, mm revisited

  18. Phenotyping late allograft deteriorationb

  19. Late allograft loss- What do we know and what to do- R. Mannon • IF/TA- asso with TGF, chronic CNIT, Ab, “chronic inflammation” - final pathway • “Healing” – regeneration/fibrosis • Phases- initiation/fibrogenesis/matrix phase • Endothelial/microvascular injury critical • Myofibroblasts – from marrow? Ciculating fibrocytes, renal, tubular cells/EMT • EMT predictive OR NOT • Are useful animal models • Targets- mono/macro, EMT, collagen sythesois, ? • RX – less CNI, ?IS, control of BP, proteinuria; anti-fibrotic

  20. Etiology of late allograft loss - DEKAF Study- A. Matas • Multi-center – cross-sectional “troubled kidneys”, prospective • New deterioration with bx • CAN, CNIT – no predictive value- many “CNIT” had Ab, C4d • Cluster using non-redundant Banff scores- (I, g. ct. cv. Mm, ah. Tatr)- prognostic • C4d and/or , iatr asso with worse outcome • Metabalomics on urine – IF vs IF+I • Outlined future studies

  21. Role of CNI toxicity for late loss B. Nankivell • Review of CNI origin, functional and structural effects- acute toxicity, vasoconstriction, chronic structural • Mechs- mitochondrial injury, giant ER- blockade of cyclophilin/FKB protein leads to stress, mis-folding of proteins • Effects on microvasculature – reflected in ah • Ah- proportional to CNI dose, precedes HTN, no asso with blood glucose • Progression – ah to gs • CNIT one of several factors leading to graft loss,, cumulative risk over time, some individuals more sensitive • NO IDEAL HISTOLOGICAL MARKER

  22. Role of recurrent disease for late loss - F. Cosio • Zial El Zoghly et al, AJT 2009 • Late graft loss – could define cause in 90% of cases- 20% due to recurrent disease • Protocol biopsies important to make early dx, define pathogenesis • FSGS- florid early, subtle late- worst outcome • MPGN- recurrence correlated with low C3, C4 • MGN – slow evolution, subclinical, neg EM • Early intervention possible

  23. Molecular associations of IFTA M. Mengel IFTA a continuum, multifactorial “I”, inflammation in IFTA correlate with outcome IFTA, iIFTA asso with B cell, mast cell transcripts- correlated with time, dGFR IHC- i-IFTA with B cells, PC, mast cells Injury/repair signals overlap with IFTA Protocol bx- EMT signatures not seen early, similar gene sets but less signal Early predictive gene sets for later IFTA – inflammation, B cells, macrophages, injury, TGF, but also correlated with dysfunction Hope – new molecular targets of intervention in i-IFTA

  24. Chronic glomerular lesions in serial biopsies - J. Papadimitriou • Glomerular lesions of increasing importance Range of lesions – ischemia, g, cg, DM, FSGS, TM • IHC C4d+ associated with cg • Cg associated with Ab, PTCML • Cg, TM, g – bad prognostic factors • CD68+ cells in g, cg • G transitioned to normal or cg

  25. Sequential biopsies- prognosis and clinical implications - D. Seron • In studies of protocol bxs- inflam, early IFTA, IFTA+cv asso with decreased survival- histologic features independently predictive • Histology predictive and surrogate variable • Sequential bx better than 1 • Clinical + histol better than clin alone • Sequential bx- acute changes decrease, chronic increase • Combination of serial bxs- integated diagnosis increases predictive value – IFTA+SCR worst

  26. Fibrosis Scoring and Reporting R. Colvin • Review of survey – 200+ responses • Routine practice – MAS, global low power % of cortex affected by fibrosis (inc/excl), and score unaffected normal cortex • Report extent, pattern, activity (mononuclear cells), evolution, % normal • Clinical trials – add morphometry • Validation – open multicenter trial on web – native and transplant biopsies

  27. Thank you!

More Related