Strict monitoring of isoagglutinins levels is required for

ABO-incompatible living-donor kidney transplantation

Ms. C.COUAT

Department of Nephrology and Organ Transplantation

Toulouse University Hospital (France)

(Pr.N.KAMAR)

INTRODUCTION

Today: many patients still die because of a shortage in kidney transplants

In 2011, the French bioethics laws were modified and allowed the use of kidney-transplant from most potential living donors (friends, couples…)

Issue: HLA and/or ABO incompatibilities between donors and recipients

Solution: pre-operative desensitization therapy

ABO System

Discovered in 1900

Defined by three letters according to the four blood types: A, B, O, and AB

A blood type is defined by the presence of antigens on the surface of red blood

cells (RBCs) and of circulating antibodies that are not present on the RBCs, called

isoagglutinins (anti-A and anti-B)

The rules for compatibility are the same as for blood transfusion

ABO system

BLOOD TYPE ANTIGENS ON

RBC’SURFACE

ANTIBODIES

PRESENT IN

THE SERUM

AB A+B Ø

A A B

B B A

O Ø A+B

In practice

Objective? Have the best immunological conditions at transplantation

How? with specific pre-transplant desensitization protocol to limit the risk of (hyper) acute rejection

In the case of ABO-incompatibility, the desensitization protocol is defined according to the baseline pre-transplant isoagglutinin level

These levels are monitored before and after transplantation, and thereafter according of a strict monitoring protocol.

In practice (2)

Analysis method: different dilution titrations :1; ½; ¼; 1/8; 1/16 or 1; 1/5. 1/10; …

Objective: isoagglutinin level closest to 1

Target level at transplantation: < 1/8

If isoagglutinin level remains > 1/16 at transplantation high risk of antibody-mediated rejection

If the target level is not reached, surgery can be postponed and desensitization protocol pursued

Techniques of desensitization:

Apheresis

Rituximab (Mabthera®)

Immunosuppressants

Techniques of desensitization: Apheresis

Extracorporeal purification which is implemented at the same time as hemodialysis (i.e. tandem procedure) on hemodialysis days (if the patient require dialysis)

This can be repeated over several session

Done over 2 to 5 hours at a low flow rate to achieve the best hemodynamic tolerance

Can be realized using hemodialysis catheters or arterio-venous fistula, or a simple peripheral catheter if the patient has a good venous network

It is a more-time efficient method compared to other methods

Protocols of apheresis (pre-transplant)

ABREVIATIONS •DFPP: Double filtration plasmapheresis •SIA: Specific ImmunoAdsorption •SSIA: Semi-Specific ImmunoAdsorption

INCOMPATIBILITIES

ABO

ABO+HLA

LEVELS

LOW

HIGH

/

APHERESIS USED

DFPP+ or SIA

DFPP and SIA

SSIA

+SIA or DFPP

AVERAGE NUMBER OF

SESSIONS

7

15

Immunoadsorption

Techniques of desensitization: rituximab (Mabthera®)

Monoclonal antibody directed against B cells. It blocks antibodies production

Its effect is longer lasting than apheresis, i.e. several months

Techniques of desensitization: Immunosupressants

Induction therapy by RATG or anti-CD25 monoclonal antibodies

It is started 10-12 days before surgery

Triple therapy composed of :

Tacrolimus (Prograf®, Advagraf®),

Mycophenolic acid (Cellcept®, Myfortic®)

Steroids (Cortancyl®).

Desensitization : exemple of protocol (adapted Tyden)

Rituximab 375 mg/m²

Tacrolimus MMF

Corticosteroid

IA

Tran

spla

nta

tio

n

IA IA IA

D-30 D-10 D-6 D-5 D-2 D-1 In hospital Long term

Post Transplant Medical Monitoring

IA :immunoadsorption

Post operative monitoring protocol of isoagglutinins

: Isoagglutinins blood test KB : Kidney Biopsy

D1 D7 D15 D28

KB

D0

KB

M2

M3 M6 M9 M12

KB KB Depending on

evolution of

kidney function

The activity of Toulouse Organ Transplant Unit

Around 200 kidney transplantations/ year

Around 55 to 60 living donor kidney transplantations / year

Of these, 20% ABO incompatible and/or HLA incompatible

Patients Since March 2011, 59 ABOi kidney transplantations were performed in our center

59 cases :

49: ABO-incompatible

10: ABO+ HLA-incompatible

Five patients were not included in the analysis because of lack of sufficient follow-up. Hence, herein, we present the results of 54 patients

Recipients’ age : 46.8± 13.5 years

54 patients

4 transplant failures

1 vein thrombosis

1 patient initially presented with vein thrombosis (surgical treatment)

then thrombotic microangiopathy, successfully treated with

plasmapheresis (3 PE+ 4 SSIA) and Eculizumab. However, he subsequently

developed progressive chronic rejection (graft loss at 14 months)

1 patient: nephrocalcinosis ( after 7 months with 2 PE post transplant)

1 chronic rejection

ABO- incompatible kidney transplantations: Outcomes

Graft survival: 92.5%

ABO- incompatible kidney transplantations: Outcomes

0 1 2 3 4 50

20

40

60

80

100

Années

Su

rvie

gre

ffon

B

n=54 n=53 n=53 n=53 n=48 n=42 n=32 n=20 n=21

Kidney function

years

Gra

ft s

urv

ival

Acute rejection rate: 33%

ABO- incompatible kidney transplantations: Isoagglutinin outcomes

Time Isoagglutinin level

Day -30

D0

D5

D15

M1

1/16 (0-1/128)

½ (0-1/16)

½ (0-1/5)

½ (1-1/40)

½ (1-1/20)

ABO- incompatible kidney transplantations: Effect of the Isoagglutinin increase on acute rejection rate

Increase in isoagglutinin

(level)

(n=10)

No increase in

Isoagglutinin level

(n=44)

ABOi

ABOi HLAi

Acute rejection

Cellular acute rejection

Antibody-mediated rejection

Mixte acute rejection

6 (60%)

4 (40%)

5 (50%)

1 (10%)

4 (40%)

0

38 (86.4%)

6 (13.6%)

13 (29.5%)

6 (13.6%)

4 (9.09%)

3 (6.8%)

The increase of isoagglutinin level was defined as an increase of 2 titers (exemple from ¼ to 1/16)

Conclusion

ABO incompatible kidney transplantation is successful. However, the rate of acute rejection remains high and a strict monitoring of isoagglutinin levels is required

Until February 2016, bothe naturel and immun isoagglutins were measured and no difference was made between both.

Actually, we are measuring both. This may help to decrease the risk of acute rejection

Acknowledgements

Pr N.Kamar 1,2,3

Dr A.Allal 1

Mrs C. Leroux-Biben 1

1 Department of Nephrology and Organ Transplantation Toulouse University Hospital

2Université Paul Sabitier (Toulouse, France)

3 INSERM U1043, IFR–BMT, CHU Purpan, Toulouse, France