1. ABO incompatible kidney transplantation
Ulla B. Berg, Division of Pediatrics
The presentation is based on slides from Gunnar Tydén and Helena Genberg, Division of Transplantation Surgery,
Dept. of Clinical Science, Intervention and Technology,
Karolinska University Hospital Huddinge, Stockholm, Sweden

2. Reasons to increase the number of living donor renal transplants
The increasing discrepancy between the number of available deceased donor organs and the number of patients on the waiting list
The superior graft and patient survival rates obtained with living donor transplants

3. Kidney transplantations in Stockholm 1990-2002

4. Kidney transplantations in Stockholm 1990-2002
10 year survival
Graft (%) Patient (%)
Living donor
Deceased donor

5. Evolution of living donor programmes
Parents, HLA- identical or haploidentical siblings
Spouses HLA-incompatible siblings
Emotionally related donors
Non-directed donation Paired exchange
Blood group incompatible
Cross match positive

6. Oag Aag Bag AagBag 40% 45% 10% 5% anti A Ab anti B Ab
The likelihood that two unrelated individuals are:
- identical is 37.5%
- compatible is 26.75%
- incompatible is 35.75%
AagBag
no Ab 5%

7. Immunohistochemistry for detection of A antigen in a blood group A1 kidney

8. A A2
Breimer et al Transplantation 82: 479, 2006

9. Previous experience in A1 and B
AB0-incompatible kidney transplantation
Year of first transplantation:
1955: Boston, Massachussets, USA, (Hume et al.)
8/10 grafts were lost in hyperacute rejection within the first week
1960: Murray
1964 Starzl
Occassional patients survived
Overall very poor results
Therefore ABO incompatibility was considered an absolute contraindication to kidney transplantation

10. Previous experience in A2 AB0-incompatible kidney transplantation
Year of publication:
1987: Gothenburg, Sweden (Breimer, Rydberg et al) (n=23)
1987: London, UK (Welsh et al.) (n=16)
1998: Kansas, USA (Nelson et al.) (n=50)
1999: Portland, Oregon, USA (Alkhunaizi et al.) (n=15)
2001: Salt Lake City, Utah, USA (Sorensen et al.) (n=15)
Between DD kidney transplantations across the A2 barrier were performed, using regular immunosuppression
1-year graft survival was approx. 55%.

11. Previous experience in A1 and B
AB0-incompatible kidney transplantation
Year of first transplantation:
1955: Boston, Massachussets, USA, (Hume et al.)
1960: Murray
1964 Starzl
1981: Portsmouth, UK (Slapak et al.)
1982: Brussels, Belgium (Alexandre et al.) (n=26)
1989: Japan (Tanabe et al.)

12. Present experiences in a series of 26 ABO-incompatible
living donor renal allografts
Alexandre GPJ, Squifflet JP et al
Tranplantation Proceedings vol XIX no pp
donor specific platelet transfusion
plasmapheresis
splenectomy
cyclosporin A, prednisolone, azathioprine
polyclonal Abs (ALG or ATG)
substance A or B
3 not splenectomized recipients hyperacutely rejected
their grafts during the first postoperative week

13. Plasma exchange Replacement fluid (albumin, plasma) plasma
separation
blood
cells
Disadvantages:
Limited efficacy due to restrictions to the plasma volume processed.
All plasma components are reduced including coagulation factors.
Fluid replacement is necessary.
Plasma discarded

14. Lessons learned from ABO-incompatible living donor kidney transplantation: 20 years later. Squifflet JP, De Meyer M, Malaise J, Latinne D, Pirson Y, Alexandre GP. Exp Clin Transplant :
39 ABO incompatible living donor grafts
“Pretransplant therapies included platelets donor transfusion, 2 to 5 plasmapheresis sessions, cyclosporin A with or without azathioprine along with polyclonal Abs and splenectomy at the time of transplantation. After the last plasmapheresis session, when the level of 1/4 (ABO antibodies) was reached, all recipients received 5 mL of substance A or B.”
Exp Clin Transplant :

15. 39 ABOi tx
<15 y
78%
59%
>15 y
Exp Clin Transplant :208-13

16. 39 ABOi tx
Rec. <15 y
N=38
N=8

17. Protocol for AB0i transplantation in Japan
441 patients
Cessation of the Anti-A/B antibody production
Splenectomy (433)
(Cyclophosphamide)
(Deoxyspergualin)
Anticoagulation therapy
(ATG or ALG)
Maintenance triple immunosuppression
Removal of Anti-A/B antibodies
Double-filtration plasmapheresis (390)
Protein A immunoadsorption (51)
Takahashi K, et al. Am J Transplant 2004;4:1089–96

18. Double-filtration plasmapheresis
Replacement fluid (albumin + Ringers)
plasma
Plasma
fractionator
Plasma separation
filtration/ centrifugation
blood cells
IgG/IgM fraction discarded

19. Protocol for AB0i transplantation in Japan
441 patients
Cessation of the Anti-A/B antibody production
Splenectomy (433)
(Cyclophosphamide)
(Deoxyspergualin)
Anticoagulation therapy
(ATG or ALG)
Maintenance triple immunosuppression
Removal of Anti-A/B antibodies
Double-filtration plasmapheresis (390)
Protein A immunoadsorption (51)
Takahashi K, et al. Am J Transplant 2004;4:1089–96

20. ABO-incompatible kidney transplantations in Japan
N Year
Incomp. Tx
Historical controls
Takahashi K, et al. Am J Transplant 2004;4:1089–96

21. Graft survival rate according to recipient age
Takahashi K, et al. Am J Transplant 2004;4:1089–96

22. Present protocol for ABO- incompatible kidney transplantations
Removing existing ABO-antibodies
Antigen-specific immunoadsorption (GlycosorbAB0®)
Preventing rebound of ABO-antibodies
Rituximab (Mabthera®)
Tacrolimus/MMF/prednisolone
IVIG (Gammagard®)
Postop preemptive immunadsorption
Am J Transplant. (2005) 5:145-8

23. Antigen-specific immunoadsorption
Glycosorb ABO column Y Y Y Y
XXX Y Y Y Y
Transplantation 2003 ;76:

24. Present protocol for ABO- incompatible kidney transplantations
Removing existing ABO-antibodies
Antigen-specific immunoadsorption (GlycosorbAB0®)
Preventing rebound of ABO-antibodies
Rituximab (Mabthera®)
Tacrolimus/MMF/prednisolone
IVIG (Gammagard®)
Postop preemptive immunadsorption
Am J Transplant. (2005) 5:145-8

25. Anti-A1 IgG titre Time (days)
Tacrolimus/MMF/prednisolone
Rituximab 375 mg/kg
IVIG (0.5 g/kg)
Glycosorb
1:128
1:64
1:32
1:16
1:8
1:4
1:2
1:1
<1:1
Anti-A1 IgG titre
–30 –13 –6 –4 –2 Tx
Time (days)
Am J Transplant. (2005) 5:145-8

26. Am J Transplant. (2005) 5:145-8

27. AB0 -incompatible kidney transplantation using antigen-specific immunoadsorption and rituximab: a 3-year follow-up
ABO-incomp. ABO-comp.
Adults
Mean rec.age
Mean don.age
Children
Mean rec.age
Mean don.age
Grafted during the same time period
In adults: the same basic immunosuppression
Genberg H et al Transplantation 85: , 2008

28. Rejection episodes in adult kidney recipients
ABO-incomp. ABO-comp.
N=15 N=30
Acute rejection (total) 1 (7%) 4 (13%) n.s.
Antibody-mediated rej. 0 (0%) 1 (3%) n.s.
Cellular rejections 1 (7%) 3 (10%) n.s.
Chronic allograft nephrop. 0 (0%) 2 (7%) n.s.
Genberg H et al Transplantation 85: , 2008

29. Rejection episodes in child kidney recipients
ABO-incomp. ABO-comp.
N=5 N=18
Acute rejection (total) 0 (0%) 3 (17%) n.s.
Antibody-mediated rej. 0 (0%) 0 (0%) n.s.
Cellular rejections 0 (0%) 3 (17%) n.s.
Patient survival 100% 100%
Graft survival 100% %
Genberg H et al Transplantation 85: , 2008

30. Cumulative event-free survival (months) in adult kidney recipients
Event: rejection, graft loss or death
0.0
0.2
0.4
0.6
0.8
1.0
ABOi: n=15
ABOc: n=30
Using chi-square test: p=ns 12 24 36 48 60
Time after transplantation in months
Genberg H et al Transplantation 85: , 2008

31. Post-transplant infections (adults)
p=ns
Genberg H et al Transplantation 85: , 2008

32. Mean-GFR and 95% CI in adults
-comparing AB0i and AB0c kidney recipients
p=ns
Genberg H et al Transplantation 85: , 2008

33. GFR after tx in AB0c and AB0i children
GFR (ml/min/1.73 m2
Time after transplantation (years)

34. Growth after tx in AB0c and AB0i children

35. What happens to the A/B antibodies following
AB0i kidney transplantation using antigen-specific
immunoadsorption and rituximab?

36. B  O Prograf/Cellcept/Prednisolone Rituximab IVIG Glucosorb 128 64 3216 8 4 2 1
<1
-30
-13 Tx

37. A1  O Prograf/Cellcept/Prednisolone Rituximab IVIG Tx Glucosorb 12864 32 16 8 4 2 1
<1
-30
-13 Tx

38. Median Ig G, n=20
Pre tx
3 - 4
5 - 7
8 - 12
>24

39. Tx cancelled
Rituximab
Glycosorb
Follow up

40. Tx ect
Arterial thrombosis Tx
Tx ect
Venous thrombosis Tx

41. LD Tx HD
Days

42. 60 consecutive transplantations
The Stockholm/Freiburg/Uppsala experience with ABO incompatible transplantations
60 consecutive transplantations
27 A1 (A/O, A/B, AB/B)
24 B (B/O, B/A, AB/A)
9 A2 (A/O,A/B) major incompatibilities
One patient died with functioning graft after 4 months
One graft was lost in non compliance after 22 months
All the remaining 58 grafts have normal function at a
follow up of months
Tydén G et al Transplantation :

43. The Stockholm/Freiburg/Uppsala experience with LD kidney transplantations performed 2002-2006
N Actual graft Actual Follow-up
survival S-creatinine months
(mean (min-max)
ABO incomp % 127 (42-203) 17.5 (2-61)
ABO comp % 133 (53-360) 21.1 (2-63)
Tydén G et al Transplantation :

44. n Ab-titre Ab-titre Cancelled tx Mean no preop.
The Stockholm/Freiburg/Uppsala experience with ABO incompatible transplantations
n Ab-titre Ab-titre Cancelled tx Mean no preop.
range median >8 adsorp. adsorptions
Stockholm 26 1:1-1:128 1:
Freiburg 21 1:8-1:1024 1:
Uppsala 13 1:1-1:32 1:
Tydén G et al Transplantation :

45. The European experience
Sweden
Stockholm
Gothenburg
Uppsala
Malmö
Germany
Freiburg
Hannover
Berlin
Heidelberg
Mannheim
Hamburg
Stuttgart
Erlangen
Frankfurt
Bochum
The Netherlands
Rotterdam
United Kingdom
London
Birmingham
Coventry
Switzerland
Basel
Zurich
Norway
Oslo
Denmark
Copenhagen
Greece
Athens
Spain
Barcelona
Australia
Melbourne
25 centres
> 200 kidney transplantations

46. General conclusion
AB0i renal transplantation without splenectomy, can be performed with excellent results, using antigen-specific immunoadsorption in combination with a single-dose of rituximab and a single-dose of IVIG in combination with standard immunosuppression
5 year graft survival is equivalent to standard AB0 compatible living donors
Antigen-specific immunoadsorption in combination with rituximab effectively depletes anti-A/B antibodies

47. General conclusion
There is no significant rebound of anti-A/B antibodies although splenectomy is not performed
A persistent low-grade anti-A/B antibody production following AB0i kidney transplantation is common but does not have any negative impact on graft function

48. Acknowledgement
Gunnar Tydén Transplantation surgery, Karolinska University Hospital
Gunilla Kumlien Transfusion medicine, Karolinska University Hospital
Helena Genberg Transplantation surgery, Karolinska University Hospital
John Sandberg
Amir Sedigh
Torbjorn Lundgren
Lars Wennberg
Henrik Gjertsen
Ingela Fehrman Nephrology, Karolinska University Hospital
Gunnar Tufveson Transplantation, Uppsala Academic Hospital

49. Extra costs for the procedure€
Glycosorb –
Apheresis (seven sessions at €1,000) –
Rituximab (one dose)
IVIG 0.5g/kg (one dose)
Total –