1. Kidney allocation to highly sensitized patients
Focus on acceptable mismatches
Sebastiaan Heidt
Eurotransplant Reference Laboratory
EFI

2. HLA matching in kidney transplantation
HLA matching improves graft survival rate
Many transplants are performed with some degree of HLA mismatch
Collaborative Transplant Study 2010
Kidney allocation to highly sensitized patients
10-Nov-18

3. Sensitization to HLA Prior organ transplants Blood transfusion
Pregnancies
Kidney allocation to highly sensitized patients
10-Nov-18

4. Hyperacute rejection
The presence of pre-transplant donor-reactive antibodies can lead to hyperacute rejection
Pre-transplant crossmatching prevents transplantation into recipients with pre-existing donor-reactive antibodies
Patients with antibodies against many specificities rarely get transplanted
Kissmeyer-Nielsen et al., Lancet 1966
Kidney allocation to highly sensitized patients
10-Nov-18

5. Highly sensitized patients
Highly sensitized patients awaiting a renal transplant are accumulating on the waiting list (many unacceptable antigens)
Definition highly sensitized:
At least 85% PRA in two different sera excluding irrelevant antibodies
Virtual PRA of at least 85% (specificities of the HLA antibodies in context of the frequencies of the HLA antigens in the donor population)
Kidney allocation to highly sensitized patients
10-Nov-18

6. Options for highly sensitized patients
Transplant with HLA identical or compatible donor (taking into account unacceptable antigens)
Do not accept that the patient is sensitized and try to remove antibodies
Accept that the patient is sensitized and and try to stimulate the allocation of crossmatch negative donor kidneys to these patients
Kidney allocation to highly sensitized patients
10-Nov-18

7. Low chance for highly sensitized patients to be transplanted through regular allocation
Kidney allocation to highly sensitized patients
10-Nov-18

8. Poor patient survival rate for patients on dialysis
Adapted from Montgomery et al., N Engl J Med 2011
Kidney allocation to highly sensitized patients
10-Nov-18

9. Desensitization protocols
Two main desensitization protocols have been used:
Plasmapheresis with low dose IVIg (living donor transplant recipients)
high dose IVIg combined with rituximab
Many patients have early acute ABMR due to antibody rebound
Plasma cells are not depleted
Side effects due to high levels of immunosuppression
Success of desensitization is highly dependent on initial antibody levels
Kidney allocation to highly sensitized patients
10-Nov-18

10. The ET acceptable mismatch (AM) program
Basis: definition of those HLA antigens toward which the patient did never form antibodies and use this knowledge for donor selection
These antigens are called acceptable antigens and help to predict a negative crossmatch
Acceptable antigens are added to the HLA phenotype of the patient to increase chance of an organ offer
Mandatory shipment of compatible organ to AM patient
Kidney allocation to highly sensitized patients
10-Nov-18

11. AM program inclusion criteria
Inclusion criteria evaluated for each patient:
Minimum of 2 years on ET-KAS waiting list (defined by date of first dialysis)
At least 85% PRA tested by CDC in two different sera excluding irrelevant antibodies
Virtual PRA of at least 85% (antibodies detectable only by solid phase assays are only considered if explainable by immunizing event)
Kidney allocation to highly sensitized patients
10-Nov-18

12. How acceptable antigens are defined
Original method:
Consider the HLA type of negative panel donors in screening
Extensive antibody screening against a patient specific panel (donors with a single HLA-A or -B mismatch), from a pool of 20,000 HLA typed blood donors
Testing serum of patients against cells expressing only one HLA type (SAL)
Use of solid phase assays
Use of computer algorithms for determining acceptable antigens (HLAMatchmaker)
Kidney allocation to highly sensitized patients
10-Nov-18

13. Selection of acceptable antigens by CDC
A1 is an acceptable antigen
A32 and A2 are unacceptable antigens
Kidney allocation to highly sensitized patients
10-Nov-18

14. Combination of patient HLA and AM: negative crossmatch
Simplified example: HLA-C and HLA-DQ are also considered
Kidney allocation to highly sensitized patients
10-Nov-18

15. Increased chance to be transplanted
Kidney allocation to highly sensitized patients
10-Nov-18

16. Are acceptable mismatches truly acceptable?
ET-KAS AM
Pairwise log-rank, Bonferroni corrected P-values. Broad mismatches
Heidt et al., Transplant Immunol 2015
Kidney allocation to highly sensitized patients
10-Nov-18

17. 10-year graft survival ET-KAS vs. AM
Selection:
≥ 1996
Renal only
Deceased donor
≥ 1 HLA antigen mm
Pairwise log-rank, Bonferroni corrected P-values. AM vs 0-5%: 0.062, AM vs. 6-85%: 1.000
ET-KAS % AM
P-value
First Tx
42227
85.1%
250
28.8%
<
Re-Tx
7377
14.9%
619
71.2%

18. 10-year graft survival re-transplant recipients
Selection:
≥ 1996
Renal only
Deceased donor
≥ 1 HLA antigen mm
Re-transplant
Pairwise log-rank, Bonferroni corrected P-values
Kidney allocation to highly sensitized patients
10-Nov-18

19. 10-year graft survival re-transplant recipients
Selection:
≥ 1996
Renal only
Deceased donor
≥ 1 HLA antigen mm
Re-transplant
 Multivariate analysis
Pairwise log-rank, Bonferroni corrected P-values
Kidney allocation to highly sensitized patients
10-Nov-18

20. Highly sensitized patients benefit from transplantation via AM program
Multivariate analysis (Cox regression)
95% C.I. HR
Lower
Upper
P-Value
A-B-DR mm
1,2,3 (ref)
4,5,6
1.27
1.001
1.618
0.049
Tx Period
(ref)
0.62
0.506
0.771
<0.001
Donor sex
Female (ref)
Male
0.82
0.677
0.985
0.034
Recipient age
≤ 50 (ref)
> 50
0.77
0.620
0.949
0.014
Donor age
1.80
1.489
2.174
Tx via AM
No (ref)
Yes
0.71
0.564
0.891
0.003
Not significant: recipient sex, blood group donor, CIP, waiting time
Kidney allocation to highly sensitized patients
10-Nov-18

21. However, not all AM patients can be transplanted
Still some AM patients with ‘exotic’ HLA types within the ET donor population remain on the waiting list
Kidney allocation to highly sensitized patients
10-Nov-18

22. EUROSTAM project: a Europe-wide AM program
Solution: look into donor populations where the ‘exotic’ phenotype is more common
Exchange between allocation programs
The EUROSTAM project (FP7, ):
Simulation studies on basis of the HLA phenotypes in different European populations
Feasibility study which lead to an advice to the European Union on how to achieve exchange between allocation organizations
Kidney allocation to highly sensitized patients
10-Nov-18

23. Conclusions
The AM program increased the chance for a highly sensitized patient to be transplanted
The AM program has been highly successful, with over 1000 highly sensitized patients transplanted
Acceptable mismatches are truly acceptable: no match-effect
Excellent ten-year graft survival of AM patients
Second option for those that still do not receive an organ: allocation outside geographical area (EUROSTAM)
Last option for highly sensitized patients: desensitization
Kidney allocation to highly sensitized patients
10-Nov-18

24. Kidney allocation to highly sensitized patients
Focus on acceptable mismatches
The ETRL team: Thanks to:
Marian Witvliet - Screening and tissue typing
Yvonne Zoet laboratory Leiden
Geert Haasnoot - ETRL immunologists
Petra van der Kroef - EUROSTAM consortium
Anouk de Jong
Sebastiaan Heidt
Frans Claas
Kidney allocation to highly sensitized patients
10-Nov-18