Antibody Mediated Rejection and Desensitization Protocols

125 Pages·2011·11.27 MB·English

Fellows Symposium on
Transplantation Medicine

Saturday, September 24
1:00 pm - 2:00 pm

Antibody Mediated Rejection
and Desensitization Protocols
Breakout Session

Peter W. Nickerson, MD and
Milagros D. Samaniego, MD

September 23-25, 2011
Hilton DFW Lakes Executive Conference Center
Grapevine, Texas
www.a-s-t.org
September 23-25, 2011
American Society of Transplantation
Grapevine, TX
Fellows Symposium
AAnnttiibbooddyy MMeeddiiaatteedd RReejjeeccttiioonn aanndd Rejection pathways (humoralrejection)
DDeesseennssiittiizzaattiioonn PPrroottooccoollss
((PPaarrtt 11)) Endothelium
Neutrophils FcReceptor mediated binding (ADCC)
AASSTT FFeelllloowwss CCoouurrssee Mǿǿǿǿ
DDaallllaass 2233 SSeepptt 22001111 NK C’Activation (CDC)
anti-MHC-Ab C4a +C4b Platelet
microthrombi
PPeetteerr NNiicckkeerrssoonn Donor MHC I/II MAC C4d
FFllyynnnn FFaammiillyy CChhaaiirr iinn RReennaall TTrraannssppllaannttaattiioonn
PPrrooffeessssoorr ooff IInntteerrnnaall MMeeddiicciinnee aanndd IImmmmuunnoollooggyy
Effectorpathways of humoralrejection Histology
Complement activation (cid:1)cell lysis(necrosis) Neutrophils, Mǿin vessels
ADCC (cid:1)cell death (necrosis/apoptosis) Microthrombi
C4d staining in immunohistochemistry
43 yr male, 1stdeceased donor renal transplant
– Remote blood transfusion
Pre-Transplant DSA – Current / Historical Sera AHG % PRA = 0
– 1 DR and 1 A Match 4 Antigen MM
What is the risk when unrecognized? – CDC T-cell & AHG-CDC T-cell cross-match -ve
What is the natural history without induction therapy?
What is the natural history when recognized and pre-transplant Immunologic Risk:Low Decision:Transplant
treatment applied?
»Primary non-function of the graft at 24 hours
»Renal Scan showed no blood flow
»Taken to the OR and the kidney was removed
3
Peter Nickerson, MD and
Milagros D. Samaniego, MD
www.a-s-t.org 1
September 23-25, 2011
American Society of Transplantation
Grapevine, TX
Fellows Symposium
4433 yyrr mmaallee,, 11ssttddeecceeaasseedd ddoonnoorr rreennaall ttrraannssppllaanntt
HistologicDiagnosis:Antibody Mediated Rejection
––RReemmoottee bblloooodd ttrraannssffuussiioonn
––CCuurrrreenntt // HHiissttoorriiccaall SSeerraa AAHHGG %% PPRRAA == 00
––11 DDRR && 11 AA MMaattcchh
EEnnddootthheelliiuumm FFccRReecceeppttoorr ––AAHHGG--CCDDCC TT--cceellll ccrroossssmmaattcchh--vvee
AADDCCCC
PMN MMeeddiiaatteedd BBiinnddiinngg
––HHiissttoollooggiiccDDiiaaggnnoossiiss:: AAnnttiibbooddyy MMeeddiiaatteedd RReejjeeccttiioonn
aannttii--HHLLAA AAbb CC44CC11 CC’’AAccttiivvaattiioonn CCDDCC – Retrospective Flow CXM: +ve with current & remote sera
CC44aa ++CC44bb – Retrospective Flow PRA: 5% Class I HLA antibody
PPllaatteelleett mmiiccrrootthhrroommbbii
DDoonnoorr HHLLAA MMAACC CC44dd ––HHLLAA MMiissmmaattcchheedd AAnnttiiggeennss:: AA2233 BB3377 5533 DDRRBB1133
– Flow Specificity Analysis: A23 antibody (titer 8)
Manitoba Experience ( 243 Primary Transplants Jun 92 -Jun 03 )
Retrospective study in 334 patients
AHG T-cell –ve, CDC B-cell –veat transplant (No Depletion Rx)
(Flow Crosssmatch+ve Retrospective study of all consecutive transplantations
Flow Single Antigen Beads) performed between 1999-2004 (n=372)
Donor Reactive Rejection Time to AbMediated Time to
no serum available induction therapy with ATG
HLA Antibody First Month Rejection Graft Loss Graft Loss (n=13) (n=25)
Class I (15) 14 (93%) 6 (1-17) 4 (27%) 4 (1-14) final population (n=334; 90%)
all had negative T-/B-cell CDC-XM
Class II (10) 8 (80%) 5 (2-7) 3 (30%) 5 (2-9)
HLA-antibody analysis by SAFB (Luminex platform)
Controls in day-of-transplant serum
No Donor Reactive
Ab
definition of HLA-DSA by virtual XM
3 (14%)* 13 (13-19)* 0 ( 0%) * p<0.001
3rdParty HLA Ab (21) vs. Class I or II
60 (31%)* 12 (4-28)* 0 ( 0%) Outcomes
No HLA Ab (195) AMRand allograft survival
Karpinskiet al, J Am Soc Nephrology 2001:12:2807-2814
Nickerson et al, ATC Abstract #362, Am J Transplantation 2004:4:S8:257 AmicoP. Transplantation (2009) 87:1681-1688
Incidence of AMR Death-censored graft survival
55% of patients with HLA-DSA developed clinical/subclinical AMR, Patients with HLA-DSA andclinical/subclinical AMR had a 20%
but 45% of patients did not. lower death-censored graft survival at 5 years
AmicoP. Transplantation (2009) 87:1681-1688 AmicoP. Transplantation (2009) 87:1681-1688
Peter Nickerson, MD and
Milagros D. Samaniego, MD
www.a-s-t.org 2
September 23-25, 2011
American Society of Transplantation
Grapevine, TX
Fellows Symposium
Readily available parameters of HLA-DSA Amount of HLA-DSA pre-transplant and AMR
were not predictive for AMR
HLA-DSA amount pre-transplant determined by FC-XM
was not predictive for the occurrence of AMR
AmicoP. Transplantation (2009) 87:1681-1688 Burns JM. Am J Transplant 8, 2008
3366 yyrr FFeemmaallee,, 11ssttrreennaall ttrraannssppllaanntt ((lliivviinngg rreellaatteedd ((BBrrootthheerr)))) SSoolluuttiioonnss ffoorr tthhee SSeennssiittiizzeedd PPaattiieenntt
––NNoo hhiissttoorryy ooff PPrreeggnnaanncciieess oorr TTrraannssffuussiioonnss
––CCuurrrreenntt // HHiissttoorriiccaall SSeerraa AAHHGG %% PPRRAA == 00
––AAHHGG--CCDDCC CCXXMM:: TT--cceellll --vvee CCDDCC CCXXMM BB--cceellll --vvee
»»FFllooww CCXXMM:: RReemmootteeTT--cceellll --vvee BB--cceellll ++vvee
»»AAuuttoo FFllooww CCXXMM:: TT--cceellll --vvee BB--cceellll --vvee Immunomodulate Living Donor Paired Exchange
»»FFllooww PPRRAA:: 00 %% ccllaassss II 1144 %% ccllaassss IIII (Local Solution) (National Solution)
(not for everyone)
»»FFllooww SSppeecciiffiicciittyy:: DDRRββ11--0077 ((ttiittrree88 iinn ccuurrrreenntt sseerraa))
Acceptable Mismatch
(National Solution)
HHLLAA RReecciippiieenntt:: AA11 22 BB 88 88 DDRRBB111177 1177
HHLLAA DDoonnoorr:: AA11 33 BB 77 88 DDRRBB11 771177
Types of Living Donor Exchanges (Chains) LDPE as of January 14, 2011
Paired N-Way
Exchange Chain 8match cycles completed
Chain
185pairs registered: 21in first run; 100in most recent
20 non-directed donors
Domino
Chain 65transplants completed
17 Coordinated and/or managed by Canadian Blood Services 18Coordinated and/or managed by Canadian Blood Services
Peter Nickerson, MD and
Milagros D. Samaniego, MD
www.a-s-t.org 3
September 23-25, 2011
American Society of Transplantation
Grapevine, TX
Fellows Symposium
Transplanted Recipients AAcccceeppttaabbllee MMiissmmaattcchh PPrrooggrraamm
Patients with CDC PRA >85%
Blood Group # % PRA Percentage # % Months on Dialysis # %
A 30 46% 0% 27 42% 0 17 26%
B 12 18% 1 to 50% 17 26% 1 to 12 12 18% Extensively Defined HLA Ab
AB 4 6% 51 to 79% 8 12% 13 to 24 8 12%
O 19 29% 80% + 13 20% 25 to 36 8 12%
TOTAL 65 TOTAL 65 37+ 20 31% Specificity Pre-Transplant
TOTAL 65
EEuurroo--TTrraannssppllaanntt
((UUnniivveerrssiittyy ooff LLeeiiddeenn))
19 FF CCllaaaass aanndd II DDooxxiiaaddiiss
Coordinated and/or managed by Canadian Blood Services
DDoonnoorr sseelleeccttiioonn oonn bbaassiiss ooff AAcccceeppttaabbllee MMiissmmaattcchheess
Chance of every newHSP patient to receive a
suitable crossmatchnegative organ within 12 mo.
Patient: A24,31; B27,51;DR4,- and 100% PRA
AM: A25, A26, B44
Offer
[%]
Possible kidney donors:A25, A31; B27, B51; DR4
A26, A31; B27, B51; DR4
A24, A25; B27, B51; DR4
A24, A26; B27, B51; DR4
A24, A31; B44, B51; DR4
A24, A31; B27, B44; DR4
A25, A31;B44, B51; DR4
A26, A31; B44, B51; DR4
A25, A31; B27, B44; DR4
A26, A31; B27, B44; DR4
A24, A25; B44, B51; DR4
A24, A26; B44, B51; DR4 KAS AM
A25, A31; B27, B44; DR4 etc.
(( CCllaaaasseett aall.. TTrraannssppllaannttaattiioonn,, 22000044))
( Courtesy FransClaas)
EEqquuiittyy ddooeess nnoott ccoommee aatt tthhee eexxppeennssee ooff UUttiilliittyy SSttrraatteeggyy
UUssee nneeww ssoolliidd pphhaassee tteecchhnnoollooggiieess ttoo ffuullllyy ddeeffiinnee lleevveell
ooff rriisskk tthheenn pprroocceeeedd ttoo mmoodduullaattee tthhee iimmmmuunnee
ssyysstteemmpprriioorr ttoo aanndd aarroouunndd tthhee ttiimmee ooff ttrraannssppllaanntt
RReeqquuiirreess ssppeecciiffiicc ttaarrggeettiinngg ooff BB--cceellllss aanndd HHLLAA AAbb
BB--cceellll PPllaassmmaa cceellll HHLLAA AAbb
––IIVVIIGG ++ -- ++++
––PPllaassmmaa PPhheerreessiiss -- -- ++++
––RRiittuuxxiimmaabb((αα--CCDD2200)) ++++++ -- --
(( CCllaaaasseett aall.. TTrraannssppllaannttaattiioonn,, 22000044))
Peter Nickerson, MD and
Milagros D. Samaniego, MD
www.a-s-t.org 4
September 23-25, 2011
American Society of Transplantation
Grapevine, TX
Fellows Symposium
DDoonnoorr bbiiooppssyy ccvv00
FFKK550066 ™™
MMMMFF ™™
PPrreeddnniissoonnee
IIVVIIGG ((22gg//kkgg))
ccii00cctt11 aahh11 mol/L)mol/L) BBiiooppssyy
µµ
((
CreatinineCreatinine
1133..88 1111..33 99..99 FFKK TTrroouugghh LLeevveellss
ii22 iinntteerrssttiittiiaall iinnffllaammmmaattiioonn tt22 ttuubbuulliittiiss
PPTTCC iinnffllaammmmaattiioonn gg11 gglloommeerruulliittiiss
Peter Nickerson, MD and
Milagros D. Samaniego, MD
www.a-s-t.org 5
September 23-25, 2011
American Society of Transplantation
Grapevine, TX
Fellows Symposium
vv11 vvaassccuulliittiiss TT aanndd BB --cceellll mmeemmoorryy ooccccuurr ttooggeetthheerr
HHLLAA AA22
PPrreeggnnaannccyy aassssoocciiaatteedd sseennssiittiizzaattiioonn aannttii−−HHLLAA AA22 AAbb
TTrraannssppllaannttaattiioonn ((11999966)) 6622::667722
B
TTrraannssffuussiioonn aassssoocciiaatteedd sseennssiittiizzaattiioonn IIFFNNγγ
TTrraannssppllaannttaattiioonn ((11999900)) 4455::998877
Th
APC IILL--22
CTL FFaass
GGrraannzzyymmeeBB
PPeerrffoorriinn
AAnnttiibbooddyy aanndd TT--cceellll mmeeddiiaatteedd rreejjeeccttiioonn ooccccuurr ttooggeetthheerr
AAbbmmeeddiiaatteedd rreejjeeccttiioonn:: TT22 ++ TT33 TTuubbuulliittiiss5500%% ((1122//2244)) ooff ccaasseess
TTrraannssppllaannttaattiioonn ((11999966)) 6611::11558866
SSttrraatteeggyy
UUssee nneeww ssoolliidd pphhaassee tteecchhnnoollooggiieess ttoo ffuullllyy ddeeffiinnee lleevveell
ooff rriisskk tthheenn pprroocceeeedd ttoo mmoodduullaattee tthhee iimmmmuunnee
ssyysstteemmpprriioorr ttoo aanndd aarroouunndd tthhee ttiimmee ooff ttrraannssppllaanntt
XM - NO DSA
RReeqquuiirreess aapppprrooaacchheess ssppeecciiffiicc ttoo TT && BB cceellll mmeemmoorryy FCXM <300 Cl/II DSA<5,000
FCXM >300 Cl/II DSA>5,000<10,000
TT--cceellll BB--cceellll PPllaassmmaa cceellll HHLLAA AAbb
IIVVIIGG -- ++ -- ++++ AHG+ Cl/II DSA >10,000
PPhheerreessiiss -- -- -- ++++
RRiittuuxxiimmaabb -- ++++++ -- --
TThhyymmoogglloobbuulliinn ++++++ ++++ ++ --
((MM.. ZZaanndd,, TTrraannssppllaannttaattiioonn 22000055))
Summary Part I
DSA detected pre-transplant
Unrecognized portends an increase risk for
oAMR and Graft Loss
oCumulative bead MFI did not reliably predict who was at risk for AMR
XM - oRisk is independent of whether Class I or II DSA are present
NO DSA
Recognized and immune modulated still portends an increase risk for
FCXM <300 Cl/II DSA<5,000 oAMR and risk correlates with strength of FCXM and bead MFI
oTG and risk did not correlate with the strength of the FCXM andbead MFI
FCXM >300 Cl/II DSA>5,000<10,000
AHG+ No DSA pre-transplant (even if sensitized)
Cl1/II DSA >10,000 Low risk for earlyAMR and subsequent TG => should be our goal
36
Peter Nickerson, MD and
Milagros D. Samaniego, MD
www.a-s-t.org 6
September 23-25, 2011
American Society of Transplantation
Grapevine, TX
Fellows Symposium
Should we accept the offers for these patients?
A B Cw DRB1 DQ DP FCXM
Donor 1 8 7 03 (17) DRB3 02 0401
Recipient #1 1 8 7 03(17) DRB3 02 0101 B+ve
(PRA 100%)
(2ndTx)
Recipient #2 1 8 7 03(17) DRB3 02 0401 -ve
(PRA 100%)
(Pregx3)
Recipient #1 has DP*0401 DSA –Does he get the kidney?
Peter Nickerson, MD and
Milagros D. Samaniego, MD
www.a-s-t.org 7
Fellows Symposium on
Transplantation Medicine

Saturday, September 24
1:00 pm - 2:00 pm

Liver Medical Cases
Breakout Session

Kimberly Brown, MD and
Shawn J. Pelletier, MD

There are no advance slides for this session.

September 23-25, 2011
Hilton DFW Lakes Executive Conference Center
Grapevine, Texas
www.a-s-t.org
Fellows Symposium on
Transplantation Medicine

Saturday, September 24
1:00 pm - 2:00 pm

Heart Medical Cases:
Immunosuppressive
Management, Acute Rejection
Breakout Session

Maryl R. Johnson, MD and
Josef Stehlik, MD, MPH

There are no advance slides for this session.

September 23-25, 2011
Hilton DFW Lakes Executive Conference Center
Grapevine, Texas
www.a-s-t.org