POSTGRADUATE
SCHOOL OF MEDICINE
ABO INCOMPATIBLE TRANSPLANTATION
Dr WS McKane
MDSC175: Transplantation Science for Transplant
Clinicians (Online)
A MEMBER OF THE RUSSELL GROUP
CONTINUING PROFESSIONAL DEVELOPMENT
ABO Incompatible Transplantation
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ABO Incompatible Transplantation
Measuring isohaemagglutinins
Removing/modulating/inhibiting synthesis of antibody
Clinical ABOi transplantation
ABO Incompatible Transplantation
Nature of ABO antigens
•
Glycolipids and glycoproteins
•
Genetics encoded by the assembly enzymes
•
•
Glycosyl transferases
Highly complex system
•
Subtypes
•
•
E.g. A1 and A2
Core chains I-VI
•
Differentially expressed
•
Branching/non-branching chains
•
A in AB individuals not identical to A in A individuals
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ABO Incompatible Transplantation
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ABO Incompatible Transplantation
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A1 vs A2
A1 and A2
• Subtle differences is
structure
• Differences in antigen density
• A2<A1
Antibody titres to
A2 typically lower
• Risk of rejection less
• Ab removal often not needed
ABO Incompatible Transplantation
Core Chains in A/B Antigens
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ABO Incompatible Transplantation
Measuring Isohaemagglutinins
•
Tube titrations
•
Gel Card titrations
•
In development
•
ELISA
•
Flow cytometry
•
RBC
•
Beads
•
Surface Plasmon Resonance
•
TLC
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ABO Incompatible Transplantation
Tube Titrations
•
Not an automated technique
• Numerous variations
•
Recipient serum and donor RBC
• Or RBC of matched third party
•
Incubated in doubling dilutions in tubes
• At RT
•
crudely considered to assess IgM
• At 37oC with AHG
•
•
Crudely considered to measure IgG
Titre is the highest dilution with agglutination
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ABO Incompatible Transplantation
Gel Cards
Diamed system
Gel card system replaces the tubes
• Otherwise the technique the same
Generally considered to reduce error
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ABO Incompatible Transplantation
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Error In A/B Titrations
•
Inter-observer error
•
Intra observer error
•
Donor v Third part RBCs
•
Determination of the cut-off subjective
•
Titrations in one centre may not reflect results in another
•
So definition of safe cut-off impossible
ABO Incompatible Transplantation
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Error In A/B Titrations
Transplantation 2007;84: S17-S19
ABO Incompatible Transplantation
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Donor‐Specific Isohemagglutinins: Measuring The
Unknown
American Journal of Transplantation, 2012, 12: 4, 803-805
ABO Incompatible Transplantation
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Removing Antibody
Plasma exchange
Centrifugal
Immunoadsorption
Non-selective
• Protein A/C
• Therasorb
Filtration
Antigen specific
Double filtration
• Glycosorb
ABO Incompatible Transplantation
Plasmapheresis
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ABO Incompatible Transplantation
Double Filtration Plasmapheresis
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ABO Incompatible Transplantation
Immunoadsorption
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ABO Incompatible Transplantation
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ABO Incompatible Transplantation
Antibody Removal
• More selective systems
•
Remove more Ab per plasma volume processed
•
Remove more selectively
• Eg clotting cascade proteins preserved
•
•
But DFPP still removes fibrinogen
Where antigen specific (eg Glycorex)
• Remove less protective Ab
• May allow treatment of higher titres
• But also remove less complement
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ABO Incompatible Transplantation
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%reduction total IgG
IgG Removal Per Treatment
100
90
80
70
60
50
40
30
20
10
0
I-A
Double Fil.
Plasma Exch.
0
10
20
30
40
Volume plasma treated, litres
50
ABO Incompatible Transplantation
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Theoretical Advantages But No Head To Head
Trials!
ABO Incompatible Transplantation
Modulating Antibody
• Multiple potential mechanisms of action
• Anti-idiotype
• FcγR saturation
• Complement “sink”
IVIg
• Anti-adhesion molecule effect
• High dose (2g/kg)
• Usually without Ab removal +/- Rituximab
• Low dose (0.1g/kg per plasma exchange)
• Usually with Ab removal
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ABO Incompatible Transplantation
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Immunosuppressives Directed At Humoral
Immunity
Pulse steroids
Anti-metabolites
Cyclophosphamide
IVIg
Bortezomib
Lymphodepletion
• Rituximab
• Alemtuzumab
• Thymoglobulin
Eculizumab
ABO Incompatible Transplantation
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Diagnosis And Management Of
Antibody‐Mediated Rejection: Current Status And
Novel Approaches
American Journal of Transplantation, 2014
ABO Incompatible Transplantation
Bortezomib
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ABO Incompatible Transplantation
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Graft Survival After Treatment Of ABMR (Kaplan–
Meier With Log-Rank Test).
Waiser J et al. Nephrol. Dial. Transplant. 2011;ndt.gfr465
© The Author 2011. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For
Permissions, please e-mail: journals.permissions@oup.com
ABO Incompatible Transplantation
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The Use of Antibody to Complement Protein C5 for
Salvage Treatment of Severe Antibody‐Mediated
Rejection
American Journal of Transplantation 2008, 9;1, 231-235
ABO Incompatible Transplantation
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Eculizumab
Control Group (n=51)
Eculizumab Group (n=26)
Acute humoral rejection %
40
7.7*(*P<0.05 vs CTL)
Early Post-Transplant High DSA %
44 (n=22)
62.5 (n=10)
Early AMR with high DSA %
94
15*(2/13)
C4d+ staining with high DSA %
100
100
Splenectomy for AHR %
38
0*
Graft dysfunction with high DSA
(mean increase in serum
creatinine from baseline in
1st month mg/dl)
1.5
0.8*
Chronic Changes on 1 yr biopsy
TxGlomerulopathy
28% (11/39)
6.25% (1/16) p=0.15
PTCitis
62%
50%
[197] Terminal Complement Blockade in Sensitized Renal Transplant Recipients.
Mark D. Stegall, Lynn Cornell, Suresh Raghavaiah, James Gloor. von Liebig Transplant Center, Mayo Clinic, Rochester, MN
ABO Incompatible Transplantation
ABOi In Clinical Practice
•
Rituximab induction
•
Antibody removal
•
Titre cut-offs variable
•
≤1/256 IgG to attempt desensitisation
•
•
•
Possibly higher with Glycorex
≤1/8 IgG to transplant
Tac MMF Pred maintenance
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ABO Incompatible Transplantation
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John Hopkins Regime
American Journal of Transplantation 2010; 10: 1-9
ABO Incompatible Transplantation
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Outcomes after ABOi
Swedish group reported equivalent outcomes to ABOc live
donor txp
UK, US and Japanese data suggest modest excess of early
graft loss
• ? Immunological
• ? Technical (re-operation for bleeding, coagulopathy)
Manuscript
ABO Incompatible Transplantation
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US ABOi Outcomes
A)
NIH-PA Author Manuscript
omery et al.
Page 11
B)
NIH-PA Author Manuscript
FIGURE 2. (A) Patient Survival and (B) Graft Loss After LDKT, Comparing ABO Incompatible
Recipients (Dashed Line) with ABO Compatible Matched Controls ( Solid Line)
ABOc controls were matched to ABOi recipients on presence of diabetes, crossmatch status,
recipient age, year of transplant, recipient insurance type, peak percent panel reactive
antigen, and years of renal replacement therapy.
A) Patient survival B) graft loss after LDKT, comparing ABO incompatible recipients
(dashed line) with ABO compatible matched controls (solid line)
Transplantation. Author manuscript; available in PMC 2013 March 27.
Transplantation. 2012 March 27; 93(6): 603-609
ABO Incompatible Transplantation
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Japanese ABOi Results Improving
Transplantation Reviews 27 (2013) 1–8
ABO Incompatible Transplantation
Early AMR after ABOi
Transplantation Reviews 27 (2013) 1–8
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ABO Incompatible Transplantation
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C4d Positivity Is The Norm After ABOi
Transplantation Reviews 27 (2013) 1–8
ABO Incompatible Transplantation
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Anti-A/B Titres After ABOi
Generally nil after
Variable rebound in
neonatal transplantation
adults
• Peripheral tolerance
• Typically low levels or
Accommodation
• Where anti-A/B
even none in Swedish
rebound but graft is
data
stable
Transplantation 2008; 85: 1745-1754
ABO Incompatible Transplantation
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AMR Risk After ABOi
15% in largest US study
Correlation with titre rebound rather than starting titre
American Journal Transplantation 2010; 10: 1247-1253
ABO Incompatible Transplantation
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Current Controversies In ABOi
Is a
splenectomy
ever
needed?
Is Rituximab
necessary?
Is post-op
Ab removal
necessary
Why is there
a modest
increase in
early graft
loss?
ABO Incompatible Transplantation
ABOi Summary
• Anti-A/B titres not easily reproducible
•
New techniques may help
• Good short and medium term results
•
AMR and CTG risk acceptable
• Areas of uncertainty
•
Antibody removal technique
•
Immunosuppression
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FACULTY OF HEALTH & LIFE SCIENCES – CPD
Institute for Learning & Teaching
Faculty of Health & Life Sciences
Room 2.16A, 4th Floor
Thompson Yates Building
Brownlow Hill
Liverpool
L69 3GB
www.liv.ac.uk/learning-and-teaching/cpd
A MEMBER OF THE RUSSELL GROUP