Kidney allocation in the UK David Turner PhD, FRCPath, Lead for H&I Services, Scottish National Blood Transfusion Service, Edinburgh, UK

34% 32% 26% 12% 40% 55%

Allocation of deceased donor organs HLA type performed (~4 hours) Recipient identified by ODT, vXM / crossmatch performed (~5 hours); if NEGATIVE transplant goes ahead (if positive risk management / or veto?) ~7000 patients awaiting an organ tx, inc kidney, pancreas, heart, liver. ODT matching algorithm produces a matching run and organs are offered out across the UK cadaveric donor

National Kidney Allocation Scheme (2006 NKAS) All kidneys from DBD allocated by national rules -: Tier A: 000 mismatched paediatric patients, HSP or DR homozygous Tier B: 000 mismatched paediatric patients Tier C: 000 mismatched adult patients, HSP or DR homozygous Tier D: 000 mismatched adult patients + paediatric patients – favourably matched [100,010,110] Tier E: All other eligible patients Within Tiers, patients prioritised by point score: Waiting time points: 1 point for each day on list HLA match & age points combined: max 3500 Age difference points: -0.5*(donor-recipient age diff)2 Location points: 900 same centre, 750 local area HLA homozygous points: HLA-B 100, HLA-DR 500 Blood group points: -1000 for B patients when donor is O PHASING IN 6

HSP & the 2006 NKAS HLA-A,B,DR Mismatches HSP Level 1 000 HSP prioritised in Tiers A and C Level 2 0 DR & 0/1 B mm HSP considered if: local to donor or antibody profile completely defined Level 3 0 DR & 2 B mm or 1 DR & 0/1 B mm HSP considered Level 4 1 DR & 2 B mm or 2 DR mm Kidneys not offered through 2006 NKAS

Revised Specificities used for HLA matching HLA-A: 1, 2, 3, 9, 10, 11, 19, 28, 29, 36, 43, 80 (n=12) HLA-B: 5, 7, 8, 12, 13, 14, 15, 16, 17, 18, 21, 22, 27, 35, 37, 40, 41, 42, 46, 47, 48, 53, 59, 67, 70, 73, 78, 81, 82, 83 (n=30) HLA-DR: 1, 103, 2, 3, 4, 5, 6, 7, 8, 9, 10 (n=11) <2% frequency in donor pool, with close counterparts based on serological reactivity/sequence data

HLA defaults used for matching in national allocation

2006 National Kidney Allocation Scheme Results of 8 years of the 2006 National Kidney Allocation Scheme

Waiting times of adult transplant patients % transplants 1998 scheme 2006 scheme

HLA mismatch levels of adult transplant patients HLA mm level % transplants 1998 scheme 2006 scheme

Transplant HLA mismatch by age Transplants (2006 scheme, years 1-8) 000 mm 0 DR & 0/1 B mm 0 DR & 2 B mm or 1 DR & 0/1 B mm 347 478 790 1192 1053 720 178 7396 HLA level Due to points system in allocation, younger patients get better matches (Levels 1,2)

Ethnicity of adult transplant patients % transplants 1998 scheme 2006 scheme

Transplants achieved through antigen defaulting Transplant due to defaulting % transplants Ethnicity

Change to the kidney allocation scheme Agreed by UK KAG that patients waiting >7yrs would get absolute priority in the deceased donor allocation scheme Applies to both DBD and DCD allocation schemes Introduced 3rd Sept 2014

Summary HLA matching important in 2006 UK National Kidney Allocation Scheme Poorly matched grafts avoided: [1 DR+ 2 B mm] [2 DR mm] Points score gives HLA match a greater weight for younger patients than older patients: Younger patients are receiving well-matched transplants Fully national scheme & more flexible approach to HLA matching More transplants for: Long waiting patients Homozygous patients Young adults Difficult to match patients, including HSP and ethnic minority patients Excellent one year graft survival, no increase in cold ischemia time

DCD Kidney Allocation- 3rd September 2014

Background >40% kidneys are from DCD Organs donated for transplantation are a national resource Kidney allocation should be open, objective and transparent DBD kidneys -Formalised national allocation scheme for both kidneys DCD kidneys - Non-standardised local arrangements Some centres already sharing DCD kidneys e.g: North Thames area, Edinburgh and Glasgow Local sharing arrangements may reflect difficulty in performing two same centre concurrent kidney transplants

2014 DCD kidney sharing scheme One kidney retained locally, second kidney shared regionally Both kidneys prioritised according to the 2006 NKAS principles To avoid significant changes to centre activity, donor age criteria will apply to manage the ‘phasing-in’ process

DCD donor kidney sharing regions Region Patients listed North 1911 (30%) Midlands 1642 (25%) London 1704 (27%) South West 1100 (17%) Gla Edi New Bel Lee Liv Man Shef Not Lei Cam Bir Cov Car Oxf Bri NT ST Por Ply

Recent discussion on allocation changes In 2015 the UK KAG chair requested a review of the current allocation scheme Various workstreams, including H&I

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?

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

Working group exploring.... Influence of HLA matching on outcome Broad matching as current algorithm e.g. DR1-DR9 Matching at the HLA split level e.g HLA-DR1-18 Defaulting of rare HLA specificities Incorporation of additional loci- HLA-C and DQ Matching for HLA epitopes Influence of HLA matching on Ab production Via analysis of UK data looking at AgMM, aaMM, EpMM, EMM

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

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

Conclusions of H&I Working Group Require extended typing of donors to include DPB1,DQA to reduce pos XM Maintain HLA matching in future allocation scheme, but perhaps based on number of MM across A,B,C,DR,DQ Remove HLA matching criteria for HSP For HSP consider cRF% at which patients receive priority in the algorithm Time from listing when patients receive priority Scale of priority