1. 2015 Kidney Allocation Task Force HLA Working Group

2. HLA Working Group Membership
Co-Chairs
Susan Fuggle, David Turner
H&I Members
Richard Battle, Martin Barnardo, David Briggs, Derek Middleton, Tracey Rees, Craig Taylor, Bob Vaughan
Clinical Members
Sian Griffin, Vasilis Kosmoliaptsis, Nizam Mamode, Carmelo Puliatti, Nick Torpey, Chris Watson
NHSBT Statistics and Scientific Support
Lisa Bradbury, Chloe Brown, Rachel Johnson, Laura Pankhurst, Linda Shelper

3. Terms of Reference
Is the current HLA typing repertoire and resolution appropriate?
What would be the consequences of a change in typing repertoire in terms of complexity and cost of donor/recipient HLA typing?
Are the current HLA matching criteria appropriate?
Is there a role for epitope matching (to minimise antibody formation)?
How should unacceptable specificities be listed and used in allocation?

4. Terms of Reference
Is the current HLA typing repertoire and resolution appropriate?
What would be the consequences of a change in typing repertoire in terms of complexity and cost of donor/recipient HLA typing?
Are the current HLA matching criteria appropriate?
Is there a role for epitope matching (to minimise antibody formation)?
How should unacceptable specificities be listed and used in allocation?

5. Repertoire and Resolution of HLA typing
Required repertoire agreed for 2006 NKAS
Currently includes:
HLA-A,B,C,DR,DQ
Intermediate level of resolution
Clinical requirement for donor HLA-DP typing to ensure efficient organ allocation
Patients have registered unacceptable HLA-DP specificities
Agreed by KAG, but not currently funded

6. Positive crossmatches: 2010-15
Year
Kidneys Allocated
Positive crossmatch n= %
2010
976 36
3.7
2011
938 26
2.7
2012
956 23
2.4
2013
1138 25
2.2
2014
1180 24
2.0
2015
1112 16
1.4
Total
6300
150

7. Reasons for a Positive Crossmatch: 2010-15 n=1505% 5% 1% 2% 3%
54/150 (36%) +ve crossmatches caused by specificities, DP, DQA and some DR alleles, outside the required minimum resolution

8. Repertoire and Resolution of HLA typing
Living Donor Kidney Sharing Scheme
Donors HLA-DP typed, taken into account in the algorithm
Laboratories are typing deceased donors for HLA-DP, because of the recognised clinical need
about 80% donors routinely typed
Not currently used in allocation

9. Repertoire and Resolution of HLA typing
Working group recommend repertoire and resolution of donor HLA typing should be extended
Details of resolution to be agreed
Resource implications to be discussed

10. Terms of Reference
Is the current HLA typing repertoire and resolution appropriate?
What would be the consequences of a change in typing repertoire in terms of complexity and cost of donor/recipient HLA typing?
Are the current HLA matching criteria appropriate?
Is there a role for epitope matching (to minimise antibody formation)?
How should unacceptable specificities be listed and used in allocation?

11. Current HLA matching criteria
Working group exploring:
Influence of HLA matching on transplant outcome
Broad matching as current algorithm e.g. DR1-DR9
Matching at the HLA split level e.g HLA-DR1-18
Incorporation of additional loci- HLA-C and DQ
Matching for HLA epitopes
Immunogenicity of epitopes
Vasilis Kosmoliaptsis, Craig Taylor
Considering defaulting of rare HLA specificities

12. Cohort 1 year graft survival: 1 April 2009 – 31 March 2014
Includes DBD & DCD transplants
Includes 1st graft and re-graft kidney only transplants
Excludes incompatible transplants
Adult only transplants
Transplants in the UK

13. Cox Regression Modelling
Are the mismatched variables significant when added into a statistical model which allows for other known important factors in graft survival?
A Cox proportional hazards regression model was fitted, adjusting for
Recipient unit Dialysis status at registration
Primary renal disease (grouped) Financial year of transplant
Recipient gender CRF at transplant (grouped)
Recipient age CIT hrs (grouped)
Recipient blood group Donor age
Recipient ethnicity Donor type
The outcome variable was graft survival at 1 or 5 years.

14. Cox Regression Modelling (1)
Including failures in first 30 days
Excluding failures in first 30 days
Description
Level
1 year (09-14)
5 year (06-10)
1 year (09-14) HR P
Number of mismatches to A
1.00
1 or 2
1.32
0.02
1.19
0.07
0.3
0.1
Number of mismatches to B
1.73
0.0001
1.36
0.002
1.79
0.004
1.47
0.001
Number of mismatches to DR
1.23
0.03
1.25
0.008
1.03
0.8
1.24
Number of mismatches to DR/DQ
0/0
0/1,2
1.11
0.6
1.13
0.5
1.31
1.08
0.7
1,2/0
1.07
0.90
1.06
1,2/1,2
0.006
1.34
1.18
1.35
0.007
Number of mismatches to B/Cw
1.86
1.10
2.36
0.0002
0.08
1.46
0.05
2.20
1.56
0.0004
1.84
1.55
0.003

15. Cox Regression Modelling (2)
Including failures in first 30 days
Excluding failures in first 30 days
Description
Level
1 year (09-14)
5 year (06-10)
1 year (09-14) HR P
HLA Level 1
1.00 2
1.73
0.003
1.17
0.2
1.60
0.08
1.28
0.1 3
2.06
0.0001
1.49
0.001
1.72
0.04
0.002 4
1.89
0.01
1.45
1.75
1.64
Total mismatches
1-3
1.37
0.03
1.41
0.3
1.35
4-6
2.25
0.0002
1.62
0.0008
1.59
0.005
7-10
2.32
1.94
0.05
2.01
0.004
linear
1.11
1.09
1.10

17. Terms of Reference
Is the current HLA typing repertoire and resolution appropriate?
What would be the consequences of a change in typing repertoire in terms of complexity and cost of donor/recipient HLA typing?
Are the current HLA matching criteria appropriate?
Is there a role for epitope matching (to minimise antibody formation)?
How should unacceptable specificities be listed and used in allocation?

18. Role for epitope matching (to minimise antibody formation)
Antibody formation post Tx is related to HLA Ag mismatch/epitope load
Recent papers show HLA Ab production associated with
number of HLA Ag MM (Kosmoliaptsis et al, Kidney Int 2014; 86:1039)
number of aa MM
number of eplet MM (Kosmoliaptsis et al, AJT 2016)
electrostatic MM
Questions:
analyses required to inform use in allocation
feasibility in the near future

19. Terms of Reference
Is the current HLA typing repertoire and resolution appropriate?
What would be the consequences of a change in typing repertoire in terms of complexity and cost of donor/recipient HLA typing?
Are the current HLA matching criteria appropriate?
Is there a role for epitope matching (to minimise antibody formation)?
How should unacceptable specificities be listed and used in allocation?

20. Median wait to transplant for
adult patients
2½ years
Calculated Reaction Frequency
Number of patients
registered
Waiting time (days)
Median % CI
0-84%
7917
963
85-94%
344
1577
95-99%
377
2138
1870 – 2406
100%
164
2424
2072 – 2776
TOTAL
8802
1016
6½ years

21. Sensitisation of long waiting patients (>7yrs)
Transplanted: 1 Sep 14 – 31 Jan 2016
Waiting list: as at 1 Sep 2014 and 1 Feb 2016 N= N= N=
Sensitisation
100%
99%
95-98%
85-94%
0-84%

22. Median waiting time to transplant
Apr 06 - Mar 10

23. Initial Considerations
Current policy - level 4 mismatched kidneys [2DR or 2B, 1DR] are not allocated, limits access for HSP
Remove HLA matching criteria for these patients
Consider
cRF% at which patients receive priority in the algorithm
Time from listing when patients receive priority
Scale of priority
Ensure suitable offers are accepted

24. 2015 Kidney Allocation Task Force HLA Working Group work ongoing……