ABO Incompatible Tx What Are the Best Protocols?

Maarten Naesens, MD PhD

Nephrology and Renal TransplantationUniversity Hospitals Leuven

7th International Conference: Living Donor Abdominal Organ TXSeptember 26th 2014 – Padova - Italy

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 A1.o Average waiting time in Belgium is 3 years for a deceased donor

kidney transplantation of blood group O.

Options in your center: - Wait list for deceased transplantation- Paired exchange program- ABO-incompatible transplantation

3

Oag

anti A Abanti B Ab

AagBag

no Ab

Aag

(A1 ~36%, A2 ~9%)anti B Ab

Bag

anti A ab

40%

5%

45% 10%

The likelihood that two unrelated individuals are:- identical is 37.5%- compatible is 64.25%- incompatible is 35.75%

The likelihood that two unrelated individuals are:- identical is 37.5%- compatible is 64.25%- incompatible is 35.75%

First succesfull ABO-incompatible transplantused minimal immunosuppression!

Starzl et al Surgery 1964

Case 1: B -> A1 rejection, successfully treated

• Case 2: A -> AB: OK

• Case 3: A -> O: death due to sepsis; graft biopsy showed “rejection”

Plasmapheresis + splenectomy to allow for ABO-I transplantation

Alexandre et al Transplant Rev 1991

or B

+ splenectomy

Plasmapheresis + splenect. + anticoagulationto allow for ABO-I transplantation

Takahashi et al Am J Transplant 2004

Splenectomy can be replaced by pretransplant rituximab administration

Gloor et al Transplantation 2005

Plasma separation

Plasma discarded

blood cells

plasma

Replacement fluid(albumin + Ringers)

Plasma-exchange removes immunoglobulinsbut also complement and coagulation factors

Plasma separation

filtration/centrifugation

Replacement fluid(albumin + Ringers)

IgG/IgM fraction

discarded

blood cells

plasma

Plasmasepar.

Double-filtration plasmapheresis (DFPP) allows treating higher plasma volumes

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

Plasma-exchange or immunoadsorption:not different for graft outcome

Opelz et al Transplantation 2014 (in press)

74%

26%

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!!

Clinical protocols for ABO-incompatible transplantation evolved over time

Tacrolimus or cyclosporineAzathioprine

Methylprednisolone

TacrolimusMycophenolate

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

?

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

XMIso

rituximab <1:16basiliximab

basiliximab

tacrolimus + mycophenolate + corticosteroids

…

ABO-I transplantation has excellent outcome in routine clinical practice

Opelz et al Transplantation 2014 (in press)

ABO-I transplantation has excellent outcome but higher mortality at 1 year

Opelz et al Transplantation 2014 (in press)

P<0.0597.0% vs. 98.6%

Graft outcome is no longer considered for choice of therapy in ABO-I transplantation

Side effects

ComplicationsLogistic issues

Cost Availability

Graft outcome

ABO-incompatible transplantationassociates with higher complication risk

Lentine et al Transplantation 2014 (in press)

ABO-incompatible transplantationassociates with higher infection risk

Opelz et al Transplantation 2014 (in press)

1.4%

0.5%

Cost* of ABO-incompatible transplantationdepends on the specific protocol

Adsor

bers

Dispos

ables

Rituxim

abIV

IG

Human

albu

min

Total

Cost (

EUR)€ 0

€10 000

€20 000

€30 000

€40 000

€50 000

€60 000

€70 000

John Hopkins (plasmapheresis)Heidelberg (non-specific IA)Stockholm (specific IA)

1 yr of HD

* Belgian context

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.

Thank you!

maarten.naesens@uzleuven.be