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

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updates banff 07

Updates- Banff 07

Issues from the Banff 07 meeting

focal vs diffuse c4d parmjeet randhawa
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
total inflammation ti score michael mengel
“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
isolated v lesion banu sis ed kraus
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
alternative ah scoring aah v broeker
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
significant of 0 time bx c legendre
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
classification ppv nephropathy v nickeleit mihatsch
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
relationship of tg to c4d and amr b sis
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?
c4d with minimal histology m haas
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
early cg detection b nankivell
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
role of c4d fixing ab in amr h regele
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
prognostic factors in amr d glotz
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
does graft accomodation occur j gloor
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
protocol bx in abo i k tanabe
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
controversies in dx of amr m samaniego
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
cg and other glomerular lesions m haas
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
late allograft loss what do we know and what to do r mannon
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
etiology of late allograft loss dekaf study a matas
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
role of cni toxicity for late loss b nankivell
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
role of recurrent disease for late loss f cosio
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
molecular associations of ifta m mengel
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

chronic glomerular lesions in serial biopsies j papadimitriou
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
sequential biopsies prognosis and clinical implications d seron
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
fibrosis scoring and reporting r colvin
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