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Transplantation of Immunologically High-risk
Recipients with Donor-specific Antibody but who are Crossmatch Negative
to Their Donors
Transplantation of Immunologically High-risk
Recipients with Donor-specific Antibody but who are Crossmatch Negative
to Their Donors
Ronald H. Kerman, PhDProfessor of Surgery
Director, Histocompatibility and Immune Evaluation Laboratory
Division of Immunology & Organ TransplantationThe University of Texas Medical School at Houston
We used to allocate donor organs
based upon the HLA antigen
match between donor and
recipient
We used to allocate donor organs
based upon the HLA antigen
match between donor and
recipient
We can now identify the presence of
HLA-Abs and their Ag specificities.
Can this information help in improving
pairing of donors to recipients?
Does the virtual XM work?
We can now identify the presence of
HLA-Abs and their Ag specificities.
Can this information help in improving
pairing of donors to recipients?
Does the virtual XM work?
Are All Antibodies Bad?Are All Antibodies Bad?
Pre-formed HLA Ab Adversely Affects:
Equity
• Prolongs wait-time for first or re-transplants• Disadvantages Women• Disadvantages African Americans
Survival
• Increased incidence of death while waiting
HLA antibodies are bad for transplant
recipients.
-Paul Terasaki
Non-HLA antibodies may also be bad
(anti-endothelial, vimentin, MICA, MICB
and others).
HLA antibodies are bad for transplant
recipients.
-Paul Terasaki
Non-HLA antibodies may also be bad
(anti-endothelial, vimentin, MICA, MICB
and others).
HLA antibodies instantly kill a kidney:
hyperacute rejection
State of preimmunization is detected by HLA antibodies
HLA antibodies are associated with acute early rejection
HLA antibodies instantly kill a kidney:
hyperacute rejection
State of preimmunization is detected by HLA antibodies
HLA antibodies are associated with acute early rejection
Lefaucheur et al. Am J Trans; 8:324, 2008Lefaucheur et al. Am J Trans; 8:324, 2008
8-Year Graft Survival
4-11
4-11 Banu Sis et al. ATC, 2010Banu Sis et al. ATC, 2010
DSA titer
SCr
FCXM
Rejection
DSA titer
SCr
FCXM
Rejection
Group 1
1:1024
1.4
Neg
No
Group 1
1:1024
1.4
Neg
No
Group 2
1:32
2.8
Pos
Yes
Group 2
1:32
2.8
Pos
Yes
Clinical Relevance of the XMClinical Relevance of the XM
Dolly Tyan (Stanford University)
MethodsC1q Assay Based on the Single Ag Bead Technology
MethodsC1q Assay Based on the Single Ag Bead Technology
Dolly Tyan (Stanford University)
High Specificity of C1q Assay
Are we trading the old allocation system
(with it’s problems) for a new allocation
system with problems of it’s own we do
not yet appreciate?
Are we trading the old allocation system
(with it’s problems) for a new allocation
system with problems of it’s own we do
not yet appreciate?
What is the real XM outcome for patients with identified donor-specific antigen that were ruled out because of the virtual crossmatch?
What is the frequency of these patients?
What is the real XM outcome for patients with identified donor-specific antigen that were ruled out because of the virtual crossmatch?
What is the frequency of these patients?
A positive (+) pretransplant (Tx) donor specific
crossmatch (XM) has been a contraindication to
transplant. Current testing methodologies allow for
performance of sensitive flow cytometry
crossmatches (FCXMs) and detection of IgG HLA
antibodies (Abs) and their antigen specificities.
Data obtained by these assays must be evaluated to
not only identify non-reactive recips but to determine
the clinical significance when recips display (+)
results.
A positive (+) pretransplant (Tx) donor specific
crossmatch (XM) has been a contraindication to
transplant. Current testing methodologies allow for
performance of sensitive flow cytometry
crossmatches (FCXMs) and detection of IgG HLA
antibodies (Abs) and their antigen specificities.
Data obtained by these assays must be evaluated to
not only identify non-reactive recips but to determine
the clinical significance when recips display (+)
results.
To understand the clinical correlation of these tests
we retrospectively evaluated Flow-PRA, FCXM, HLA
Ab specificities and Ab titers of 300 pre-Tx sera from
recips of deceased renal allograft donors
transplanted after negative (-)
AHG-XMs.
To understand the clinical correlation of these tests
we retrospectively evaluated Flow-PRA, FCXM, HLA
Ab specificities and Ab titers of 300 pre-Tx sera from
recips of deceased renal allograft donors
transplanted after negative (-)
AHG-XMs.
HLA Ab, Specificity, Titer and FCXMHLA Ab, Specificity, Titer and FCXMHLA AbHLA Ab
DSDS Non-DSNon-DS TiterTiter
FCXMFCXM
(+)(+) (-)(-)
1.1. 15*15* ++ ++ ≥256≥256 (+)(+)
4444 ++ ++ ≤16≤16 (-)(-)
1010 ++ ++ ≤16≤16 (+)(+)
2.2.
3.3.
2323 00 ++ ≥256≥256 (+)(+)5.5.
3535 00 ++ ≤16≤16 (-)(-)
3030 00 ++ ≤16≤16 (+)(+)
2222 00 ++ ≥256≥256 (-)(-)4.4.
6.6.
7.7.
9696 00 00 -- (-)(-)
2525 00 00 -- (+)(+)
8.8.
9.9.
NN
24 mo.GraftSurvival
24 mo.GraftSurvival
0%0%
91%91%
60%60%
74%74%
89%89%
74%74%
86%86%
95%95%
76%76%
2-yr GS of 91% for (-) vs 72% for (+) FCXM P<0.0012-yr GS of 91% for (-) vs 72% for (+) FCXM P<0.001
HLA Ab, Specificity, Titer and FCXMHLA Ab, Specificity, Titer and FCXM
HLA AbHLA Ab
DSDS Non-DSNon-DS TiterTiter
FCXMFCXM
(+)(+) (-)(-)
12 mo.GraftSurvival
12 mo.GraftSurvival
4444 ++ ++ ≤16≤16 (-)(-) 91%91%2.2.
NN
44/300 = 15% of total recipients
(+) DSA , but a (-) FCXM
44/54 ( 81.5% ) DSA (+) recips were XM (-)
44/300 = 15% of total recipients
(+) DSA , but a (-) FCXM
44/54 ( 81.5% ) DSA (+) recips were XM (-)
18 A-A; 11 women; 6 Hispanic (25/44 = 57%)18 A-A; 11 women; 6 Hispanic (25/44 = 57%)
HLA Ab, Specificity, Titer and FCXMHLA Ab, Specificity, Titer and FCXM
HLA AbHLA Ab
DSDS Non-DSNon-DS TiterTiter
FCXMFCXM
(+)(+) (-)(-)
12 mo.GraftSurvival
12 mo.GraftSurvival
2323 00 ++ ≥256≥256 (+)(+) 87%87%5.5.
3030 00 ++ ≤16≤16 (+)(+) 87%87%7.7.
2525 00 00 -- (+)(+) 88%88%9.9.
NN
78/300 = 26% of total recipients
(-) DSA but a (+) FCXM
78/231 ( 38% ) DSA (-) recips were XM (+)
78/300 = 26% of total recipients
(-) DSA but a (+) FCXM
78/231 ( 38% ) DSA (-) recips were XM (+)
ConclusionsConclusionsConclusionsConclusionsConclusionsConclusionsConclusionsConclusions
1. High titer DS-HLA Ab and a (+) FCXM are bad!
2. The presence of (low titer) DS-HLA Ab and a (-) FCXM is not a contraindication to transplant (vs a virtual crossmatch).
3. Absence of DS-HLA Ab does not guarantee a (-) FCXM.
1. High titer DS-HLA Ab and a (+) FCXM are bad!
2. The presence of (low titer) DS-HLA Ab and a (-) FCXM is not a contraindication to transplant (vs a virtual crossmatch).
3. Absence of DS-HLA Ab does not guarantee a (-) FCXM.
4. The binding of IgG to donor targets results in poor clinical outcome.
5. Negative FCXMs result in excellent clinical outcome (whether DS, non-DS HLA or non-HLA Abs are present).
4. The binding of IgG to donor targets results in poor clinical outcome.
5. Negative FCXMs result in excellent clinical outcome (whether DS, non-DS HLA or non-HLA Abs are present).
ATC 2007 Abstract: Am J Trans, 2007
Transplantation of DSA+/FCXM-Kidney Recipients
1. We previously reported the 85% 1-year graft survival for 26 DSA(+)/FCXM(-) renal allograft recipients treated with Basiliximab, Thymo, CNI, Steroids.
2. From January, 2008 we prospectively treated 33 DSA(+)/FCXM(-) renal allograft recipients with:
Thymoglobulin induction (7 – 14 days) 5 – 10 plasmapheresis followed by Rituxan/IVIgCyclosporine, MMF, Steroids
3. There were 15 male / 18 female recipients; 11 African-American, 4 Hispanic, 11 Caucasian, 2 Asian; 7 - 1o, 7 re-transplant recipients.
• In order to transplant these patients DSA is not listed for calculated PRA.
• Patients receive no points for PRA, but are crossmatched for every donor.
• If cytotoxic and flow crossmatches are negative, DSA protocol is initiated.
All recipients were ABO compatible and transplanted following negative AHG and FCXMs.
Sera tested included pre-transplant (days 0-7) highest historic PRA, and an intermediate serum of 3-6 months pre-transplant.
All but 1 recipient had positive DSA in pre-transplant and other prior sera.
1 recipient had positive DSA in a historic serum, but not pre-transplant.
Transplantation of DSA+/FCXM-Kidney Recipients
Results: post-transplant (2 – 37 months, mean 16.2):97% graft survival (32/33)100% patient survivalMean SCr of 1.5 mg/dL (n=32)1 Non-immunological graft loss at 21 monthsSCr of 8.7 mg/dL (n=1)
10 early rejections: 2 ACR, 8 AbMR (all C4d+ ) at 7 – 21 days post-transplant
2 delayed rejections at 8 months (ACR) and 12 months (mixed) post-transplant
Transplantation of DSA+/FCXM-Kidney Recipients
Pre-transplant Immune Studies:
1. 14 recipients with HLA Class I DSAs; titers from 1:2 – 1:128
DSA-specific MFIs of 1,275 – 7,213 (median MFI 2,386)
2. 19 recipients with HLA Class II DSAs; titers from 1:1 – 1:128
DSA-specific MFIs of 1,390 – 24,317 (median MFI 5,796)
The pre-transplant class of HLA Ab, DSA, DSA titers or
DSA MFI were not predictive of rejection or graft loss
(median MFI 3,408).
Post-Tx PRA and DSA Follow-up
N=33 (Follow-up of 2 to 30 mos. post-Tx)
5 - No DSA
10 - recips w/ class I DSA titers (1:1 - 1:64)
15 - recips w/ class II DSA titers (1:64 - 1:128)
2 year old African-American male, living-related transplant from mother. Managed with excellent renal function on cyclosporine / prednisone until auto accident led to loss of graft at age 17.
On wait-list 4 years with 95% PRA Class I and II.
Donor Antigen Specificities removed from UNOS listing. Within 1 week transplanted (10/15/08) with DSA(+), crossmatch(-) deceased donor.
Plasmapheresis x 1 week, thymoglobulin, CsA, MPA.
No rejection, creatinine 1.8 mg (2/8/11).
Conclusions
These results suggest that patients with surrogate HLA antigen-bead identified Ab may be successfully transplanted as long as the donor-specific FCXMs are negative and the patients receive aggressive immunosuppression.
These patients should not be excluded from transplantation (because of virtual crossmatch considerations) and may not need pre-transplant desensitization.
Graft Survival vs. CrossmatchGraft Survival vs. Crossmatch
Graft Survival vs. CrossmatchGraft Survival vs. Crossmatch
To Treat or Not to Treat ?
AbMR
To Treat or Not to Treat ?
Identifying Clinically Relevant Ab
1. During a clinical event or by biopsy
2. During a stable clinical course
3. Methods identifying the presence and specificity
of Abs do not characterize the function of the Ab.
4. The binding of an Ab in a XM is a functional assay
which may reflect the amount of Ab, the Ab
avidity for the target epitope or other factors.
Thoughts
The binding of patient Ab to Ag-coated beads is not a binding to donor Ag, but a third party, surrogate Ag.The fact that this might not correlate to crossmatch activity is not surprising. All Abs are not bad!We do not understand everything we see clinically. We have problems, but since they are identified we can solve them and take advantage of the new technology.
Thoughts
The binding of patient Ab to Ag-coated beads is not a binding to donor Ag, but a third party, surrogate Ag.The fact that this might not correlate to crossmatch activity is not surprising. All Abs are not bad!We do not understand everything we see clinically. We have problems, but since they are identified we can solve them and take advantage of the new technology.
Non-HLA AbsNon-HLA Abs
HLA Ab (Class I / Class II)HLA Ab (Class I / Class II)
Relevant ConsiderationsRelevant Considerations
(+) Donor-specific XM(+) Donor-specific XM
IgG AbIgG Ab
To identify the presence of clinically relevant Abs in recipient sera vs donor antigens(HLA, Non-HLA)
Determine antibody specificity (HLA, Non-HLA)
Determine antibody titer
XM by most sensitive method (FCXM)
Knowledge of the patient’s antibody status can help us to understand the crossmatch results
To identify the presence of clinically relevant Abs in recipient sera vs donor antigens(HLA, Non-HLA)
Determine antibody specificity (HLA, Non-HLA)
Determine antibody titer
XM by most sensitive method (FCXM)
Knowledge of the patient’s antibody status can help us to understand the crossmatch results
Role of the HLA Laboratory:Role of the HLA Laboratory: