Summary of clinical protocols for ABO incompatible kidney transplantation - presentation at the Belgian Society of Nephrology

1. ABO incompatible
transplantation
Maarten Naesens, MD PhD
Nephrology and Renal Transplantation
University Hospitals Leuven
BVN meeting, December 15th, 2016

2. Case:
o 60-year old female with blood group O with end-stage
renal disease, dialysis start imminent.
o Husband is suitable candidate for kidney donation, but
donor blood group A.
o Average waiting time in Belgium is 3 years for a deceased
donor kidney transplantation of blood group O.

3. Wait list for deceased donor transplantation
Living donor paired exchange program
ABO incompatible transplantation

4. O
AB
A
(A1 ~36%, A2 ~9%) B
40%
5%
45%
10%
The likelihood that two
unrelated individuals are:
- identical is 37.5%
- compatible is 64.25%
- incompatible is 35.75%

5. Bohmig et al Nat Rev Nephrol 2015

6. Bohmig et al Nat Rev Nephrol 2015

7. Bohmig et al Nat Rev Nephrol 2015

8. Bohmig et al Nat Rev Nephrol 2015

9. Hyperacute rejection

10. First successful ABO-incompatible transplant
used minimal immunosuppression!
Starzl et al Surgery 1964
Case 1: B -> A
1 rejection, successfully treated
• Case 2: A -> AB: OK
• Case 3: A -> O: death due
to sepsis; graft biopsy
showed “rejection”

11. Plasmapheresis + splenectomy
to allow for ABO-I transplantation
Alexandre et al Transplant Rev 1991
or B
+ splenectomy

12. Plasmapheresis + splenectomy
to allow for ABO-I transplantation
Alexandre et al Transplant Rev 1991
or B
+ splenectomy

13. Plasmapheresis + splenectomy
to allow for ABO-I transplantation
Alexandre et al Transplant Rev 1991

14. Plasmapheresis + splenect. + anticoagulation
to allow for ABO-I transplantation
Takahashi et al Am J Transplant 2004

15. Splenectomy can be replaced by
pretransplant rituximab administration
Gloor et al Transplantation 2005

16. Key elements of recipient desensitisation for
ABOi transplantation are now well established
Bohmig et al Nat Rev Nephrol 2015

17. Plasma
separation
Plasma discarded
blood
cells
plasma
Replacement fluid
(albumin + Ringers)
Plasma-exchange removes immunoglobulins
but also complement and coagulation factors

18. Plasma
separation
filtration/
centrifugation
Replacement fluid
(albumin + Ringers)
IgG/IgM
fraction
discarded
blood cells
plasma
Plasma
separ.
Double-filtration plasmapheresis (DFPP)
allows treating higher plasma volumes

19. Replacement fluid
(albumin + Ringers)
Ig
discarded
blood cells
plasma Plasma
adsorber
Specific or non-specific immunoadsorption is
replacing plasmapheresis (in EU)
Plasma
separation
filtration/
centrifugation

20. Replacement fluid
(albumin + Ringers)
Ig
discarded
blood cells
plasma Plasma
adsorber
A/B specific
adsorber
Non-specific
Ig adsorber
Specific or non-specific immunoadsorption is
replacing plasmapheresis (in EU)
Plasma
separation
filtration/
centrifugation

21. Specific or non-specific immunoadsorption is
replacing plasmapheresis (in EU)
Non-specific
Ig adsorber

22. Specific or non-specific immunoadsorption:
not different for graft outcome
Morath et al Transplantation 2012
VERY LOW NUMBERS IN SINGLE CENTER
TO MAKE ANY CONCLUSION!!

23. Plasma-exchange or immunoadsorption:
not different for graft outcome
Opelz et al Transplantation 2014
74%
26%

24. Rituximab is not necessary
but likely beneficial for ABO-incompatible TX
Opelz et al Transplantation 2014

25. Clinical protocols for ABO-incompatible
transplantation evolve over time
Tacrolimus or cyclosporine
Azathioprine
Methylprednisolone
Tacrolimus
Mycophenolate
Methylprednisolone
Splenectomy Rituximab
Plasmapheresis, double-filtration plasmapheresis, non-specific
immunoadsorption, specific immunoadsorption (pre and post TX)
Intravenous immunoglobulin (IVIG)
1980
Earlier
Trials
1990 2000 2010
preTX
?

26. Current clinical protocol for
ABO-I transplantation in Leuven
Highest
Isoagglutine
titer
Start day IA
(-X)
Number of IA
sessions
 1:8 -5 4
1:16 -6 5
1:32 -8 6
1:64 -9 7
1:128 -11 8
1:256 -13 9
1:512 -14 10
non-antigen-specific IA
day -35 -30 -X TX 4
XM
Iso
rituximab <1:16
basiliximab
basiliximab
tacrolimus + mycophenolate + corticosteroids
…

27. ABO-I transplantation has excellent outcome
in routine clinical practice
Opelz et al Transplantation 2014

28. ABO-I transplantation has excellent outcome
but higher mortality at 1 year
Opelz et al Transplantation 2014
P<0.05
97.0% vs. 98.6%

29. Histology of 1-yr protocol biopsies in
ABO-I vs. +XM vs –XM kidney transplantation
Bentall et al Transplantation 2014

30. Histology of 5-yr protocol biopsies in
ABO-I vs. standard kidney transplantation
Bentall et al Transplantation 2014

31. Recurrence of the antibodies, but acceptance
of the graft = accommodation?
• Active process: anti-apoptotic gene upregulation??
Not confirmed
• Dependent on Ig isotype class?? Natural vs. de novo ABO
antibodies? Single-center small studies.
• New hypothesis: Absence of donor-reactive T cells and
absence of activation of antigen-presenting cells?
Bentall et al Transplantation 2014

32. Side effects
Complications
Logistic issues
Cost Availability
Graft
outcome

33. ABO-incompatible transplantation
associates with higher complication risk
Lentine et al Transplantation 2014

34. ABO-incompatible transplantation
associates with higher infection risk
Opelz et al Transplantation 2014
1.4%
0.5%

35. Living donors have better outcome than
deceased donor (SCD or ECD)
% death-censored graft survival
Time after transplantation (months)
De functionele overleving van transplantnieren
hangt af van het donortype
25% graft loss
by 2 years
Eurotransplant data 2003-2010
Death-censored graft survival

36. Country-wide* access to ABOi transplantation
could increase the number of LDs to 75/year
* Belgian context
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015
0
200
400
600
Year
Numberoftransplantationsperyear
Deceased
Living
(N=57 in 2015; 11%)
+ 30%

37. The additional cost* of ABO-incompatible
transplantation depends on the specific protocol
* Belgian context
Adsorbers
D
isposables
R
ituxim
ab
IVIG
H
um
an
album
in
Total C
ost (EU
R
)
0
10000
20000
30000
40000
50000
60000
70000
80000
Cost(€)
John Hopkins (plasmapheresis)
Heidelberg(non-specific IA)
Cost of 1 year dialysis
Stockholm(specific IA)

38. Conclusion
• ABO-incompatible living donor kidney transplantation has equal
outcome as ABO-compatible transplantation (i.e. better than
deceased-donor kidney transplantation).
• There are many different protocols used, and outcome is
excellent in all.
• Due to absence of controlled trials comparing the different
protocols, no best protocol can be put forward.
• The risks associated with intensified immunosuppression
needs to be weighed against the benefit of a pre-emptive living
donor kidney.
• The financial cost of desensitization is low in comparison to
chronic dialysis.

39. Thank you!
maarten.naesens@uzleuven.be