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POSTGRADUATE SCHOOL OF MEDICINE A MEMBER OF THE RUSSELL GROUP

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Presentation on theme: "POSTGRADUATE SCHOOL OF MEDICINE A MEMBER OF THE RUSSELL GROUP"— Presentation transcript:

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

2 ABO Incompatible Transplantation
Measuring isohaemagglutinins Removing/modulating/inhibiting synthesis of antibody Clinical ABOi transplantation

3 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

5 A1 vs A2 A1 and A2 Antibody titres to A2 typically lower
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

6 Core Chains in A/B Antigens

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

8 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

9 Gel Cards Diamed system Gel card system replaces the tubes
Otherwise the technique the same Gel card system replaces the tubes Generally considered to reduce error

10 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 Error In A/B Titrations
Transplantation 2007;84: S17-S19

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

13 Removing Antibody Plasma exchange Immunoadsorption Centrifugal
Filtration Double filtration Immunoadsorption Non-selective Protein A/C Therasorb Antigen specific Glycosorb

14 Plasmapheresis Circuit diagram of PE Plasmaflo OP Anticoagulant
Blood pump Plasma separator Substitution fluid Waste Pump Circuit diagram of PE

15 Double Filtration Plasmapheresis
Plasmaflo OP Anticoagulant Blood pump Plasma separator Substitution fluid Waste Pump Circuit diagram of DFPP Cascadeflo EC component Double Filtration Plasmapheresis

16 Immunoadsorption CAN MAKE DIAGRAM FROM PREVIOUS TWO DIAGRAMS

17

18 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 IgG Removal Per Treatment

20 Theoretical Advantages But No Head To Head Trials!

21 IVIg 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 Immunosuppressives Directed At Humoral Immunity
Pulse steroids Anti-metabolites Cyclophosphamide Lymphodepletion Rituximab Alemtuzumab Thymoglobulin IVIg Bortezomib Eculizumab

23 Diagnosis And Management Of Antibody‐Mediated Rejection: Current Status And Novel Approaches
Therapeutic modalities for ABMR. ABMR, antibody‐mediated rejection; APC, antigen‐presenting cell; IVIG, intravenous immunoglobulins. © This slide is made available for non-commercial use only. Please note that permission may be required for re-use of images in which the copyright is owned by a third party. American Journal of Transplantation, 2014

24 Bortezomib

25 Graft Survival After Treatment Of ABMR (Kaplan–Meier With Log-Rank Test).
Graft survival after treatment of ABMR (Kaplan–Meier with log-rank test). In patients treated with bortezomib in addition to standard therapy (n = 10), graft survival at 18 months after treatment was 60% as compared to 11% in patients who received rituximab in addition to standard therapy (n = 9). 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 The Use of Antibody to Complement Protein C5 for Salvage Treatment of Severe Antibody‐Mediated Rejection Time course of treatment initiation and renal function during the peritransplant period. (A) Renal function and cytotoxic crossmatch titer during the posttransplant course. (B) Desensitization and treatment time‐line. CXM = cytotoxic crossmatch; UOP = urine output; αC5 = anti‐C5 antibody (eculizumab); αCD20 = anti‐CD20 antibody (rituximab); PP = plasmapheresis; MMF = mycophenolate mofetil; FK = tacrolimus. © This slide is made available for non-commercial use only. Please note that permission may be required for re-use of images in which the copyright is owned by a third party. American Journal of Transplantation 2008, 9;1,

27 Eculizumab Acute humoral rejection % 40 7.7*(*P<0.05 vs CTL)
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 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

28 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 John Hopkins Regime American Journal of Transplantation 2010; 10: 1-9

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

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

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

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

35 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 AMR Risk After ABOi 15% in largest US study
Correlation with titre rebound rather than starting titre American Journal Transplantation 2010; 10:

37 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 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 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 A MEMBER OF THE RUSSELL GROUP


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