ABO Incompatible Kidney Transplantation

Federico Oppenheimer

Unitat de Trasplantament RenalServei de Nefrologia i Trasplantament Renal

Hospital Clínic de Barcelona

oppen@clinic.ub.es

ABO incompatible Kidney Transplantation

Historical Review

� 50’s and 60’s: Hume, Murray and Starzl reported first experiences with ABOi

Long-term graft survival was observed in some initial cases

� 70’s: First ABOi (A2 -> O) in Gothenburg

� 80’s: Guy Alexandre (Leuven): (A1 / B -> O) (Paediatric recipients)

� 1989-1992: Multicentre Clinical Trial in Japan: 51 patients

� 1989-2001: Japanese experience with 441 transplants

� 2001 Rituximab to replace splenectomy

� 2001 Specific immunoadsorption to replace plasma exchange

� 2004-2010: Several reports from Japan, USA, and Europe

Takahashi et al. Am J Transplant 2004

1. Isoagglutinins removal:

Extracorporeal immunoadsorption (Biosynsorb®) 51 patientsA. Pre-transplant plasma exchange (2-3 times)

Post-transplant plasma exchange: according to isoagglutinine titres or AMR

1. Conventional immunosuppression1. CyA (66%) – Tacro (34%)2. Azathioprine or Mizoribine3. Prednisone

1. Splenectomy: 98% patients

1. Anticoagulation therapy: nafamostat mesilate -> platelet antiaggregation therapyto prevent intragraft disseminated intravascular coagulation223 patients (51%)

Takahashi et al. Am J Transplant 2004

Treatment Procedure

Takahashi et al. Am J Transplant 2004

Anticoagulation (nafamostat mesilate) and platelet antiaggregation therapy

Causes of graft failure

Chronic graft nephropathy 37Death with a functioning graft 33Acute rejection 28Accelerated rejection 13Stop immunosuppression 5FSG 5IgA 3Disseminated intravascular coagulation 3Other

Takahashi et al. Am J Transplant 2004

Thaiss F, Atherosclerosis Supplements 10 (2009) 133.–136

The techniques currently used to eliminate preformed ABOantibodies.

Thaiss F, Atherosclerosis Supplements 10 (2009) 133.–136

Rituximab is given once or twice beforeABOi kidney transplantation

(Splenectomy is not routinely performed)

Evaluation of Immunosuppressive Regimens in ABO-Incompatible Living Kidney Transplantation — Single Center Analysis

Ishida et al., Am J Transplant 2007

Evaluation of Immunosuppressive Regimens in ABO-Incompatible Living Kidney Transplantation — Single Center Analysis

Ishida et al., Am J Transplant 2007

Evaluation of Immunosuppressive Regimens in ABO-Incompatible Living Kidney Transplantation — Single Center Analysis

Ishida et al., Am J Transplant 2007

Am J Transplant 2004

Am J Transplant 2005

Am J Transplant 2005

Glycosorb®

IgM pre IgM post

1/128 1/8

ABO Incompatible Kidney Transplantations Without Splenectomy, Using Antigen-Specific Immunoadsorption and Rituximab

Gunnar Tydén, Gunilla Kumlienb, Helena Genberga, John Sandberga, Torbjörn Lundgrena and Ingela Fehrmanc

1 dose of Rituximab Tacrolimus MMF Prednisone

Inmunoadsorption (Glucosorb) IvIg(1 dose)

Tydén et al. Am J Transplant 2005

0% Acute

Rejection

Implementation of a Protocol for ABO-Incompatible Kidney Transplantation A Three-Center Experience With 60 Consecutive Transplantations

Tydén et al. Transplantation 2007

Takahashi K, Clin Exp Nephrol 2007

C4d in ABO-Incompatible Allografts:Rejection or Accommodation

Gloor et al. Am J Transplant 2006

Figure 1: Percent of recipients who develop transplant glomerulopathy 1 year after transplantation divided according to the severity of the pathologic process (cg = 0, white bars; cg = 1, light gray bar; cg = 2, darker gray bar; cg = 3, black bar).

Gloor et al. Am J Transplant 2006

Hospital Clínic BarcelonaKidney Transplant Activity

35%

12%2%0%14%

37%

Kidney Kidney - Pancreas Kidney - Liver

Kidney - Heart NHBD Living

2009 - Kidney Transplant ActivityHospital Clínic de Barcelona

n= 162

Treatment Protocol

• D -10 MMF 500 mg bid

• D - 8 Rituximab 375 mg/m2

MMF 1000 mg bid

• D -7 1st Glucosorb Immunoadsorption

• D -7 Tacrolimus 0.15 mg/kg casa 12 horas -> 10-15 ng/ml

• D -5 2nd Glucosorb Immunoadsorption

• D -3 3rd Glucosorb Immunoadsorption

• D -1 4th Glucosorb Immunoadsorption

Policlonal IvIg 500 mg/kg

• D 0 ATG 1.5 mg/kg / Simulect 20 mg

Metil-Prednisolone 500 mg

• D 2 5th Glucosorb Immunoadsorption

• D 4 6th Glucosorb Immunoadsorption

• D 7 7th Glucosorb Immunoadsorption

Clinical Case

L.S.F.Female 33 yrs. oldABO: OLupus NephritisHaemodialysis in 1989Deceased donor Tx in 1990Irreversible acute rejection on day 15PRA 100%10 years on waiting list in Hospital Clinico Barcelona

2 HLA-identical sisters (28 and 30 yrs old)Negative XMABO incompatible (Donor A1 -> Recipient O)

0

2

4

8

16

32

64

128

256

512

-5 TX 5 10 15 20 25 30 35 40 45 50 55 60

18 sesiones IA (6/12)

7 sesiones RP03.Oct.2006

Rituximab 3 dosis

IGIV 4 dosis

Tacrolimus 11.2 ± 3.8 ng/mL

0

1

2

3

4

5

6

7

8

9

Títulos IsA Cr (mg/dL)

Ds pos-trasplante

16/Octubre/2006 (D 13 pos-tx)

1ª Biopsia injerto renal

Patient 1 (LL.S.F.) Post Tx Day 13

Patient 1 (LL.S.F.) Post Tx Day 23

RB RB RB

Patient 1 LL.S.F.

Patient 1 LL.S.F.

RB RB RB

Patient 1 (LL.S.F.) Post Tx Month 6

Patient 1 LL.S.F.

Tacrolimus -> Everolimus 1.35 mg/dL

RB RB RB

Donor Blood Group

Recipient Blood Group

0

10

20

30

40

50

60

70

80No sensitized

Low sensitized

Sensitized

Anti-HLA sensitization

ABOi Living Donor Transplants - Results

Grupo sanguíneoA B AB

Grupo sanguíneoO AB B

2006 – 2011: 29 ABOi Tx

29 ABOi Kidney Transplants2 AMR (1 graft loss)1 Thrombosis1 Death with functioning graft

0

30

60

90

120

150

180

210

240

270

Baseline Tx 1 w 2 w

Isoagglutinine titres

ABOi Living Donor Transplants - Results

Pat Numb Donor ABO

Patient ABO Ig/M/IgG Baseline Ig/M/IgG Tx Ig/M/IgG D +7

Ig/M/IgG D +15

Pre/Post Sessions

1.

LL.S.F.

A O 32/128 2/4 32/32 64/64 6/3

2.

M-A.E.R.

A O 256/64 4/4 2/2 2/1 7/7

3.

J-F.L.C.

A1+ O+ 32/32 8/16 4/4 4/4 6/3

4.

M.T.

A1+ O+ 64/128 16/32 4/4 4/8 4/3

5.

V-L.G.O.

A1+ O+ 64/64 16/16 8/8 8/8 5/3

6.

A.S.N.

A1+ O+ 64/128 8/8 2/2 8/8 6/3

7

J-M.A.I.

A1+ B+ 16/8 4/4* 16/8 8/8 6/6*

8

F.R.

A1B+ B+ 16/16 0/0 0/0 0/0 5/0

9.

J-A.A.A.

A1- O+ 16/32 8/16** - - 5/1**

10.

V.V.F.

B- A1+ 4/2 4/4 2/1 4/1 0/0

11.

D.M.G.

A1+ O+ 128/256 8/16 2/8 11/2

Pat Numb Donor ABO

Patient ABO Ig/M/IgG Baseline Ig/M/IgG Tx Ig/M/IgG D +7

Ig/M/IgG D +15

Pre/Post Sessions

12.

V-L.A.

A1+ O+ 64 8 4 4

13.

J.P.E.

A+ O+ 32 4 2 4

14.

R.A.M.

A1+ B+ 16 4 2 4

15.

M-D.C.G.

AB+ A2+ 16 2 32 -> 128 2

16.

J.I.C.

B+ A1+ 32/32 2 2

Pat Numb Donor ABO

Patient ABO Ig/M/IgG Baseline Ig/M/IgG Tx Ig/M/IgG D +7

Ig/M/IgG D +15

Pre/Post Sessions

L.A.C. A1- O+ 128/512 No No No 14/-

J.G. A1B+ O+ 128/256 No No No 16/- *

M-D.J. B+ O+ 64/64 – 128/256 No No No 12/-

* Bortezomib

11,2

60,2 59,3

68,4 70,5

53,8

1821,9 22,4 21,8

17,5

64,6

61,663,6

100,2

78

24,6 22,2

0

20

40

60

80

100

120

Basal Discharge 1m 3m 6m 12m 18m 24m 48m

GFR 24hr Proteinuria (gr/dl)

N: 15 15 13 13 13 6 5 2 2

GFR (ml/min) and proteinuria

ABOi Living Donor Transplants - Results

Patient and Graft Survival

Death-Censored Graft Survival

Acute Rejection

Adverse events

Acute rejection 4p (1A, 1B, AMR, AMR)Graft thrombosis 1p

Varicella-Zoster meningitis 1p (25 months post Tx)

Transient BKV cytology 1p SV40Death 1p (hipovolemic shock)