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ABO INCOMPATIBLE TRANSPLANTATION Dr WS McKane MDSC175: Transplantation Science for Transplant Clinicians (Online) POSTGRADUATE SCHOOL OF MEDICINE A MEMBER.

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Presentation on theme: "ABO INCOMPATIBLE TRANSPLANTATION Dr WS McKane MDSC175: Transplantation Science for Transplant Clinicians (Online) POSTGRADUATE SCHOOL OF MEDICINE A MEMBER."— Presentation transcript:

1 ABO INCOMPATIBLE TRANSPLANTATION Dr WS McKane MDSC175: Transplantation Science for Transplant Clinicians (Online) POSTGRADUATE SCHOOL OF MEDICINE A MEMBER OF THE RUSSELL GROUP CONTINUING PROFESSIONAL DEVELOPMENT

2 2 ABO Incompatible Transplantation Measuring isohaemagglutininsRemoving/modulating/inhibiting synthesis of antibodyClinical ABOi transplantation

3 3 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

4 4 ABO Incompatible Transplantation

5 5 A1 vs A2 A1 and A2 Subtle differences is structure Differences in antigen density A2

6 6 ABO Incompatible Transplantation Core Chains in A/B Antigens

7 7 ABO Incompatible Transplantation Measuring Isohaemagglutinins Tube titrations Gel Card titrations In development ELISA Flow cytometry RBC Beads Surface Plasmon Resonance TLC

8 8 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 37 o C with AHG Crudely considered to measure IgG Titre is the highest dilution with agglutination

9 9 ABO Incompatible Transplantation Gel Cards Diamed system Otherwise the technique the same Gel card system replaces the tubesGenerally considered to reduce error

10 10 ABO Incompatible Transplantation 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

11 11 ABO Incompatible Transplantation Error In A/B Titrations Transplantation 2007;84: S17-S19

12 12 ABO Incompatible Transplantation Donor‐Specific Isohemagglutinins: Measuring The Unknown American Journal of Transplantation, 2012, 12: 4,

13 13 ABO Incompatible Transplantation Removing Antibody Plasma exchange CentrifugalFiltrationDouble filtration Immunoadsorption Non-selective Protein A/C Therasorb Antigen specific Glycosorb

14 14 ABO Incompatible Transplantation Plasmapheresis

15 15 ABO Incompatible Transplantation Double Filtration Plasmapheresis

16 16 ABO Incompatible Transplantation Immunoadsorption

17 17 ABO Incompatible Transplantation

18 18 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

19 19 ABO Incompatible Transplantation IgG Removal Per Treatment

20 20 ABO Incompatible Transplantation Theoretical Advantages But No Head To Head Trials!

21 21 ABO Incompatible Transplantation Modulating Antibody Multiple potential mechanisms of action Anti-idiotype FcγR saturation Complement “sink” 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 IVIg

22 22 ABO Incompatible Transplantation Immunosuppressives Directed At Humoral Immunity Pulse steroidsAnti-metabolitesCyclophosphamide Lymphodepletion Rituximab Alemtuzumab Thymoglobulin IVIgBortezomib Eculizumab

23 23 ABO Incompatible Transplantation Diagnosis And Management Of Antibody‐Mediated Rejection: Current Status And Novel Approaches American Journal of Transplantation, 2014

24 24 ABO Incompatible Transplantation Bortezomib

25 25 ABO Incompatible Transplantation Graft Survival After Treatment Of ABMR (Kaplan– Meier With Log-Rank Test). Waiser J et al. Nephrol. Dial. Transplant. 2011;ndt.gfr465 © The Author Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please

26 26 ABO Incompatible Transplantation The Use of Antibody to Complement Protein C5 for Salvage Treatment of Severe Antibody‐Mediated Rejection American Journal of Transplantation 2008, 9;1,

27 27 ABO Incompatible Transplantation Eculizumab [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

28 28 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

29 29 ABO Incompatible Transplantation John Hopkins Regime American Journal of Transplantation 2010; 10: 1-9

30 30 ABO Incompatible Transplantation 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)

31 31 ABO Incompatible Transplantation US ABOi Outcomes Transplantation March 27; 93(6): A)Patient survival B) graft loss after LDKT, comparing ABO incompatible recipients (dashed line) with ABO compatible matched controls (solid line) A)B)

32 32 ABO Incompatible Transplantation Japanese ABOi Results Improving Transplantation Reviews 27 (2013) 1–8

33 33 ABO Incompatible Transplantation Early AMR after ABOi Transplantation Reviews 27 (2013) 1–8

34 34 ABO Incompatible Transplantation C4d Positivity Is The Norm After ABOi Transplantation Reviews 27 (2013) 1–8

35 35 ABO Incompatible Transplantation Anti-A/B Titres After ABOi Generally nil after neonatal transplantation Peripheral tolerance Variable rebound in adults Typically low levels or even none in Swedish data Accommodation Where anti-A/B rebound but graft is stable Transplantation 2008; 85:

36 36 ABO Incompatible Transplantation AMR Risk After ABOi 15% in largest US studyCorrelation with titre rebound rather than starting titre American Journal Transplantation 2010; 10:

37 37 ABO Incompatible Transplantation 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?

38 38 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

39 A MEMBER OF THE RUSSELL GROUP 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


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