U.S. changes in Kidney Allocation Match kidneys with longest survival to patients with longest survival No parallel matching for kidneys with lower survival potential Decrease discard of kidneys with lower survival potential Increased sharing different from Eurotransplant Increase transplantation for highly sensitized patients Some kidneys with long projected survival allocated to high risk patients (sensitized with long dialysis exposure) Backdated patients to dialysis start date Improved access for ethnic minorities/low SES patients Transplanting patients with long dialysis exposure where survival benefit of transplantation compared to treatment with dialysis is less certain
Kidney Allocation in the UK: Did the Last System Work? What will the next one look like? Chris Watson University of Cambridge, UK
Conflict of Interest Disclosure I have no relevant financial relationships to disclose. I will not discuss off label drug use I chair the Kidney Advisory Group of NHSBT = Kidney committee of UNOS
UK & USA: two nations divided by a common language and an oval ball You pass forwards to score a touch down We pass backwards to go forwards to score a touchdown
UK Renal Replacement Oversight: NHS BT UK population 60 million 71 Local Dialysis Centers $ UK National Health Service pays for all costs for life 23 Regional Transplant Centers
Access to the waiting list 52% of patients undergoing renal replacement therapy have a transplant Of those on dialysis 48% are listed for transplant Percentage wait-listed 100 9 0 8 7 0 0 6 0 5 0 4 3 0 2 0 0 1 0 0 UK Renal Registry 2014
UK kidney allocation: Outline How we did we get here? Oversight in the UK Where are we going next?
1989 scheme: Beneficial matching Beneficial HLA match: 000, 100, 010 mm One kidney shared Preference for child / local patient One kidney kept locally Relative Risk of graft loss 11 9 7 5 3 1 001 010 100 020 200 002 101 011 110 021 201 102 111 120 012 210 202 121 220 112 211 022 122 212 221 222 000 0 1 2 3 4 5 6 A + B + DR Mismatches 60 70 80 90 96 Estimated % surviving one year Gilks et al. Transplantation 1987;43:669 Analysis of 2282 kidney Tx in UK, 1979-84
Why not share both kidneys? Poorer outcomes of shared kidneys 1.2 RR of graft failure Balance of exchange North of England donate more kidneys South of England list more recipients
Transplant survival rate (%) 100 90 80 70 60 50 40 30 20 10 1998 scheme: Favorable matching p = 0.0001 000 000 100/010/110 Other 0DR 1 DR 2 DR 0 0 1 2 3 4 5 Time (years) since transplant Analysis of 6338 Tx in UK, 1986-93 Favorable mismatch 100, 010, 110 Both kidneys offered for 000 or favorable One kidney for non-favorable Priority Highly sensitised Children Local vs. national patient Morris et al. Lancet 1999;354:1147
Effect of favorable offering: better matching 100% % of recipients 80% 60% 40% 20% 0% 38 35 33 31 50 36 49 52 51 54 45 43 7 13 13 16 15 19 Pre-scheme year 1 year 2 year 3 year 4 year 5 Non favorable Favorable (100,010, 110) 000
Problems with favorable matching Blood group B waited longer And so ethnic minorities waited longer 100% 80% 60% 40% 20% 3 3 14 9 34 38 49 49 AB B A O Bias against HLA DR homozygotes 0% Waiting list Donor pool
Minimising HLA-DR mismatches penalises HLA-DR homozygotes 1-1-1 mismatch A1, A10 B8, B27 DR17, DR5 A1, - B8, - DR17, - Heterozygote 0-0-0 mismatch Homozygote
Homozygotes waited longer 59% 20% 21% Not Homozygous A B A & B DR A & DR B & DR A & B & DR 570 686 672 723 785 785 863 888 0 200 400 600 800 1000 Median waiting time (days)
2006 scheme aims Remove concept of ownership Share both kidneys nationally Re-evaluate role of HLA Match younger patients better than older Address existing inequalities Long waiting patients Ethnicity / Blood group homozygosity Reduce cold ischaemic times
Default rare HLA types to related common type Rare HLA types are difficult to transplant Rare HLA types defaulted to more common ones based on serological cross reaction Sequence information Consequence Improved access to first transplant May result in sensitisation and longer wait for subsequent Tx Rare specificity Related specificity % of donor pool A36, A80 A1 18 A43 A10 4 B53 B5 5 B42, B73, B81 B7 15 B59 B8 13 B82, B83 B12 18 B46 B15 7 B67 B22 2 B47 B27 5 B70, B78 B35 7 B41, B48 B40 7 DR101, DR10 DR1 10 DR9 DR4 20 DR11, DR12 DR5 8 Johnson et al. Transplantation 2010; 89: 387
Points based scheme 2006 scheme Waiting time: 1 point for each day on list HLA mismatch level & recipient age: maximum 3500
HLA mismatch and transplant survival 4 levels of mismatch 000 mismatch % transplant survival HLA-A Years post transplant HLA-B Years post transplant 0DR & 0/1 B mm 0DR & 2B mm or 1 DR & 0/1 B mm Others % transplant survival HLA-DR Johnson et al. Transplantation 2010; 89: 379 Years post transplant Years post transplant
HLA mismatch / age relation Part of a points based allocation Age & HLA mismatch More points for better matched kidney in young patient 000 mismatch 0DR & 0/1B mismatch 0DR & 2B mm or 1DR & 0/1B mm Johnson et al. Transplantation 2010; 89: 379
Other elements of scheme 2006 scheme Donor recipient age difference: -0.5 x (don - recip age) 2 Location of donor (minimise ischaemic time): 900 if same centre (23 centres, 3m population) 750 if same region (3 regions, 20m population) HLA B homozygous: 100 HLA DR homozygous: 500
Effect of current scheme on HLA matching by age group Proportion of Txs 100% 80% 60% 40% 20% 0% <18 18-29 30-39 40-49 50-59 60-69 >70 Age group Other 0DR & 2B or 1DR & 0/1B 0DR & 0/1B mm 000 mismatch
Percent 20 15 10 5 Transplants for ethnic minorities Black patients Transplants Transplant List Percent 0 20 15 10 5 0 1 2 3 4 5 6 7 8 Asian patients Year 1 2 3 4 5 6 7 8 Percent 85 80 75 70 65 White patients 1 2 3 4 5 6 7 8
% of patients on waiting list 40 35 30 25 20 15 10 5 0 Reduction in proportion of long waiting patients 38 37 35 35 14 14 31-Dec-05 31-Mar-14 8 8 5 6 <1 yr 1-3 yrs 3-5 yrs 5-7 yrs 7 yrs Waiting time
Cold ischaemic times since 2006 NHSBT 8 year review
Problems with current scheme 1. Excess of highly sensitised (cpra* >85%) patients 30 25 20 15 10 5 0 26.7 16.4 9.9 New Listing Waiting list Transplants *cpra is termed calculated reaction frequency in UK, based on reactivity to 10000 UK donors
Problems with current scheme 2: Donor & Recipient factors not accounted for Standard criteria Extended criteria NHSBT Annual Report on Kidney Transplantation 2015. http://www.odt.nhs.uk/pdf/organ_specific_report_kidney_2015.pdf
Proportion of poorer quality kidneys increasing Number of donors 2000 1500 1000 500 0 21% 256 239 280 325 961 965 977 924 363 437 504 599 694 794 1040 1044 998 999 1056 1146 2004/05 05/06 06/07 07/08 08/09 09/10 10/11 11/12 12/13 13/14 41% High risk (UKKDRI 1.35) Standard risk (UKKDRI <1.35) UKKDRI: Transplantation 2012; 93: 314. NHSBT data 1 Apr 2004 31 Apr 2014, courtesy Rachel Johnson
2000 1500 1000 Problems with current scheme: 3: It doesn t integrate DCD kidney offering DCD DBD 214 272 319 452 527 540 638 710 779 711 37% are DCD 500 932 902 871 877 881 893 894 987 1101 1121 0 2005/06 2006/07 2007/08 2008/09 2009/10 2010/11 2011/12 2012/13 2013/14 2014/15 Deceased Kidney Donors in the UK 2005/6 to 2014/15 http://www.odt.nhs.uk/pdf/organ_specific_report_kidney_2015.pdf
Discard rates for kidneys from deceased donors, 2014 % of retrieved kidneys not transplanted 30 25 20 15 10 5 0 24 19 10 Spain US UK Source: ONT Spain data, OPTN - US data, NHSBT - UK data
Discard rates for kidneys from deceased donors, 2014, by donor age 60 % of retrieved kidneys not transplanted 50 40 30 20 10 0 16 16 7 2 9 7 2 11 8 24 31 34 57 13 15 <18 18-34 35-49 50-64 65+ Donor Age Source: ONT Spain data, OPTN US data, NHSBT - UK data Spain US UK
Oversight: CUSUM monitoring O-E chart 3 month reports Triggers for graft loss & death Baseline is that center s own past performance Letter from NHSBT to explain trigger Response reviewed by NHSBT medical director Kidney committee chair NHS Commissioner Tabular CUSUM Liver Transplantation 2010;16:1119
Oversight: Publication of center specific data Waiting list Demographics Waiting time Pre-emptive listing rate Transplants Demographics (DRI; DCD/DBD; LD) Cold ischaemic time Graft and patient survival http://www.odt.nhs.uk/uk-transplantregistry/organ-specific-reports/
Survival from listing 5 year patient survival From listing: 87% (84 92%) From transplant: 89% (81 95%) 10 year patient survival from listing Median 75%
The future: beyond HLA matching Reduce sensitisation by improved matching HLA epitope Not whole antigen Electrostatic charge minimisation AJT 2013; 13: 3114 Hum Immunol 2011;72:1049
Future: Reduce offer decline rate Each offer should be the best offer for that patient
ATTOM study Access to renal Transplantation and Transplant Outcome Measures study Sample (n=6862): All incident dialysis patients in the UK in a year All new kidney & Kidney/pancreas transplants Plus matched controls
ATTOM Analyses Quality of life and quality of health Including in depth interviews with subset Clinical data on co-morbidity e.g. cardiac status Survival Health economics Analysis of unit differences in protocols and practice
Age The future: smarter offering Recipient factors Child vs. old adult Ischaemic time Life expectancy Tissue matching On dialysis Post transplant Waiting time From dialysis start Donor factors DBD and DCD HLA / Epitope / electrostatic Donor kidney quality e.g. KDPI Donor disease risk Sensitization Others, e.g. cost effectiveness Quality of life
Summary UK allocation schemes have been developed using evidence-based modeling. evolved from simply matching for HLA Take some recipient & donor factors into account evolved from offering one kidney for a beneficial match, to both kidneys going into the national pool All schemes have losers and winners. regular review and adjustment has been necessary to ensure fairness. The next scheme will further personalize offering.