2015 Kidney Allocation Task Force HLA Working Group

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

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?

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?

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

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

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

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

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

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?

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

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

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.

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

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

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?

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

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?

Median wait to transplant for adult patients 2½ years Calculated Reaction Frequency Number of patients registered Waiting time (days) Median 95% CI   0-84% 7917 963 942 - 984 85-94% 344 1577 1487 - 1667 95-99% 377 2138 1870 – 2406 100% 164 2424 2072 – 2776 TOTAL 8802 1016 995 - 1037 6½ years

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= 319 N= 147 N= 260 Sensitisation 100% 99% 95-98% 85-94% 0-84%

Median waiting time to transplant Apr 06 - Mar 10

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

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