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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,

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abo incompatible kidney transplantation

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

slide2

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
slide4

Kidney transplantations in Stockholm 1990-2002

10 year survival

Graft (%) Patient (%)

Living donor 70 85

Deceased donor 40 55

slide5

Evolution of living donor programmes

  • Parents, HLA- identical or haploidentical siblings
  • SpousesHLA-incompatible siblings
  • Emotionally related donors
  • Non-directed donationPaired exchange
  • Blood group incompatible
  • Cross match positive
slide6

40%

Oag

anti A Abanti B Ab

45%

10%

Aag

(A1~36%, A2~9%)

anti B Ab

Bag

anti A ab

The likelihood that two unrelated individuals are:

- identical is 37.5%

- compatible is 26.75%

- incompatible is 35.75%

AagBag

no Ab

5%

slide8

A1 A2

Breimer et al Transplantation 82: 479, 2006

slide9

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

slide10

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 1974-1988 23 DD kidney transplantations across the A2 barrier were performed, using regular immunosuppression

1-year graft survival was approx. 55%.

slide11

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.)

slide12

Present experiences in a series of 26 ABO-incompatible

living donor renal allografts

Alexandre GPJ, Squifflet JP et al

Tranplantation Proceedings vol XIX no 6 1987 pp 4538-4542

  • 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

slide13

Replacement fluid(albumin, plasma)

Plasma exchange

plasma

blood

cells

Plasma

separation

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

slide14

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. 2004 2:208-13.

  • “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.”

39 ABO incompatible living donor grafts

Exp Clin Transplant. 2004 2:208-13.

slide15

39 ABOi tx

<15 y

78%

59%

>15 y

Exp Clin Transplant. 2004 2:208-13

slide16

39 ABOi tx

Rec. <15 y

N=38

N=8

p rotocol for ab0i transplantation in japan
Removal of Anti-A/B antibodies

Double-filtration plasmapheresis (390)

Protein A immunoadsorption (51)

Cessation of the Anti-A/B antibody production

Splenectomy(433)

(Cyclophosphamide)

(Deoxyspergualin)

Anticoagulation therapy

(ATG or ALG)

Maintenance triple immunosuppression

441 patients 1989 - 2001

Protocol for AB0i transplantation in Japan

Takahashi K, et al. Am J Transplant 2004;4:1089–96

slide18

Double-filtration plasmapheresis

Replacement fluid(albumin + Ringers)

Plasma

fractionator

plasma

Plasma separation

filtration/centrifugation

blood cells

IgG/IgM fraction discarded

p rotocol for ab0i transplantation in japan19
Removal of Anti-A/B antibodies

Double-filtration plasmapheresis (390)

Protein A immunoadsorption (51)

Cessation of the Anti-A/B antibody production

Splenectomy(433)

(Cyclophosphamide)

(Deoxyspergualin)

Anticoagulation therapy

(ATG or ALG)

Maintenance triple immunosuppression

441 patients 1989 - 2001

Protocol for AB0i transplantation in Japan

Takahashi K, et al. Am J Transplant 2004;4:1089–96

slide20

ABO-incompatible kidney transplantations in Japan

N Year

Incomp. Tx 441 1989-2001

Historical controls 1055 1986-1995

Takahashi K, et al. Am J Transplant 2004;4:1089–96

slide21

Graft survival rate according to recipient age

Takahashi K, et al. Am J Transplant 2004;4:1089–96

slide22

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

slide23

Antigen-specific immunoadsorption

Glycosorb ABO column

Y

Y

Y

Y

XXX

Y

Y

Y

Y

Transplantation 2003 ;76:730-731

slide24

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

slide25

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 2 4 6 8 10 12

Time (days)

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

slide27

AB0 -incompatible kidney transplantation using antigen-specific immunoadsorption and rituximab: a 3-year follow-up

ABO-incomp. ABO-comp.

Adults15 30

Mean rec.age 35.1 42.4

Mean don.age 52.8 49.0

Children 5 18

Mean rec.age 8.6 7.8

Mean don.age 42.5 42.8

Grafted during the same time period

In adults: the same basic immunosuppression

Genberg H et al Transplantation 85:1745-1754, 2008

slide28

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 85:1745-1754, 2008

slide29

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% 95%

Genberg H et al Transplantation 85:1745-1754, 2008

slide30

1.0

0.8

0.6

0.4

0.2

0.0

0

12

24

36

48

60

Cumulative event-free survival (months) in adult kidney recipients

Event: rejection, graft loss or death

ABOi: n=15

ABOc: n=30

Using chi-square test: p=ns

Time after transplantation in months

Genberg H et al Transplantation 85:1745-1754, 2008

slide31

Post-transplant infections (adults)

p=ns

Genberg H et al Transplantation 85:1745-1754, 2008

slide32

Mean-GFR and 95% CI in adults

-comparing AB0i and AB0c kidney recipients

p=ns

Genberg H et al Transplantation 85:1745-1754, 2008

slide33

GFR after tx in AB0c and AB0i children

GFR (ml/min/1.73 m2

Time after transplantation (years)

slide35

What happens to the A/B antibodies following

AB0i kidney transplantation using antigen-specific

immunoadsorption and rituximab?

slide36

128

64

32

16

8

4

2

1

<1

B  O

Prograf/Cellcept/Prednisolone

Rituximab

IVIG

Glucosorb

-30

-13

Tx

slide37

128

64

32

16

8

4

2

1

<1

A1  O

Prograf/Cellcept/Prednisolone

Rituximab

IVIG

Tx

Glucosorb

-30

-13

Tx

slide38

Median Ig G, n=20

Pre tx

3 - 4

5 - 7

8 - 12

13 - 24

>24

slide39

Rituximab

Glycosorb

2003-09

Tx cancelled

Follow up

2006-05

Rituximab

Glycosorb

2003-10

Tx cancelled

Follow up

2006-03

Rituximab

Glycosorb

2005-05

Tx cancelled

Follow up

2006-03

slide40

Tx ect

Arterial thrombosis

Tx

Tx ect

Venous thrombosis

Tx

slide41

Tx

HD

Days

2007-01

2007-04

2006-01

LD

the stockholm freiburg uppsala experience with abo incompatible 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 1 - 60 months

Tydén G et al Transplantation 2007 83:1153-1155

the stockholm freiburg uppsala experience with ld kidney transplantations performed 2002 2006
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. 60 97% 127 (42-203) 17.5 (2-61)

ABO comp. 274 95% 133 (53-360) 21.1 (2-63)

Tydén G et al Transplantation 2007 83:1153-1155

the stockholm freiburg uppsala experience with abo incompatible transplantations44
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 1:32 3 4.2

Freiburg 21 1:8-1:1024 1:128 5 7

Uppsala 13 1:1-1:32 1:8 0 3.9

Tydén G et al Transplantation 2007 83:1153-1155

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

The European experience

25 centres

> 200 kidney transplantations

slide46

General conclusion

  • AB0i renal transplantation without splenectomy, canbe 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
slide47

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
acknowledgement

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

slide49

Extra costs for the procedure

  • Glycosorb 10.000 – 40.000
  • Apheresis (seven sessions at €1,000) 4.000 – 12.000
  • Rituximab (one dose) 1.800
  • IVIG 0.5g/kg (one dose) 1.000

Total 16.800 – 54.800