Renal transplantation is the most effective treatment for most patients with end-stage renal disease and demand for transplantation in most if not all countries far exceeds the number of donor kidneys available (1, 2). Living donor kidney transplantation activity has increased markedly over the last decade (1, 3) helping to address the shortfall in donor kidneys, but the majority of patients awaiting transplantation remain dependent on receiving a kidney from a deceased donor. Consequently, national and local strategies for allocating deceased donor kidneys to those listed for transplantation are of great importance and have major implications for individual patients and national healthcare systems. Kidney allocation schemes often aim to achieve a balance between equity (equal access to all recipients) and utility (maximizing the lifetime of the transplanted kidney). Devising and implementing an allocation scheme that is both fair and acceptable to patients, transplant health care workers, and wider society poses a considerable challenge. To achieve these goals, an allocation scheme should be evidence based, transparent, subject to regular audit, and be amenable to modification to reflect changes in demographics of the donor and patient population, alterations in working practice, and scientific advances. Despite the interest in this area, there is surprisingly little published literature on kidney allocation schemes and their effectiveness.
Organ sharing schemes have been central to kidney transplantation in the United Kingdom for many years (4), and in 1998, a new national kidney allocation scheme (NKAS) for deceased heartbeating (DHB) donors was introduced that remained operational until April 2006. The scheme represented a compromise between equity and utility with a bias toward utility because it was based on published evidence from a review of factors influencing transplant outcome in the United Kingdom (5, 6). This demonstrated that human leukocyte antigen (HLA) matching had a major impact on graft outcome, and as a result, the 1998 scheme was based on HLA matching, but it also included a number of other factors relevant to achieving an acceptable balance between equity and utility.
In this article, we describe the impact of the 1998 NKAS on renal transplantation in the United Kingdom over a 5-year period (1998–2003), including the rationale for, and impact of, refinements made to the scheme in that time.
The 1998 NKAS was developed and implemented by the Organ Donation and Transplantation Directorate of NHS Blood and Transplant (formerly UK Transplant). Organ Donation and Transplantation is responsible for central oversight and management of organ transplantation in the United Kingdom, including management of patient waiting lists and organ allocation, and collection and analysis of data on organ transplantation for the UK Transplant Registry, including transplant outcome and performance data.
The Role of HLA Matching in the 1998 NKAS
Evidence from the United Kingdom published in 1999 showed that transplants with no mismatches at HLA-A, -B, and -DR (000 mismatch grade) had superior survival to transplants with a maximum of one mismatch at HLA-A and -B (100, 010, and 110 mismatch grades), termed “favorably matched,” and these transplants in turn had superior survival to transplants with all other mismatch grades. These three levels of HLA mismatches formed the basis of the 1998 NKAS (Fig. 1). In general, one kidney from each donor was allocated nationally for well-matched patients (tiers 1 and 2) to maximize the benefits from HLA matching and ensure priority for highly sensitized and pediatric patients. The second kidney from each donor and kidneys for which no well-matched patients were identified were allocated by the local transplant center for one of their patients according to locally agreed criteria. Many of these kidneys were allocated through formal local allocation schemes, typically involving patients from three to five geographically proximate transplant centers on a common list. Such regional schemes varied in nature, but all included an emphasis on HLA matching of transplants.
Allocation Hierarchy Within the ThreeHLA-Matching Tiers
Figure 1 shows the various factors used to prioritize patients within each of the national matching tiers (1 and 2). In each case, pediatric patients (aged <18 years) have absolute priority over adult patients.
The approach to transplanting highly sensitized patients (HSPs) (≥85% HLA antibody panel reactive antibody) in the United Kingdom is to assign priority above other patients in tier 1 (000 mismatched patients) and, when the antibody profile has been completely specified, to give access to favorably matched virtual crossmatch negative kidneys.
HLA homozygous donors provide well-matched organs for a large pool of equally mismatched homozygous and heterozygous recipients and are a valuable source of compatible organs for sensitized and other high priority patients. To ensure that HLA-DR homozygous patients also have access to such kidneys, they have priority for HLA-DR homozygous donor kidneys in tiers 1 and 2, although this prioritization was not in place when the 1998 NKAS was first implemented.
The final ranking factor for the hierarchical part of the 1998 NKAS prioritizes patients at the nearest transplant center, or group of centers for those working as part of a regional team, avoiding unnecessary transportation of kidneys to more distant centers.
The Points Score
Equally eligible patients within the individual groups of tiers 1 and 2 of the 1998 NKAS were differentiated by a points score based on a number of factors (Table 1).
One of the secondary aims of the allocation scheme was to improve access to well-matched transplants for patients with rare HLA types relative to the national donor pool. To achieve this, a matchability points score was developed. Each patient's score was based on the number of blood group identical 000 and favorably matched donors in a pool of 10,000 UK donors. The score also took into account the patient's unacceptable HLA specificities identified through antibody screening programs and reported to the national database and, therefore, was a true reflection of the number of HLA antibody compatible donors in the national pool. The scores were calculated centrally and were set in a range of 1 (easy to match) to 10 (difficult to match). Although recognizing that it would be impossible to achieve equal access to well-matched transplants for all patients, when a suitable kidney was identified for a more difficult to match patient, the points score was designed to promote that patient above others who were easier to match and more likely to be offered an alternative well-matched kidney.
Points were also allocated for waiting time to benefit longer waiting patients, but because of the link between waiting time and difficult to match patients, this factor received only half the weighting of most others (a maximum of 5 points rather than 10).
Points for age matching between donor and recipient were introduced to limit offering of old donor kidneys to young patients and vice versa, reflecting what was observed in clinical practice.
Analysis had shown that clinical practice favored younger patients for allocation of kidneys and that, on average, donors were older than patients on the transplant list. To address this, and ensure that donor-recipient age difference points did not disadvantage younger patients, points were included for patient age.
Centers exporting more kidneys than they imported achieved a positive “balance of exchange” and attracted more points for their patients. The points were designed to keep center balances within a reasonable range without adversely affecting patient-related factors.
An important aspect of the scheme was the inclusion of points associated with sensitization status. These points were introduced to achieve more efficient organ allocation through encouraging comprehensive analysis of the patient's antibody profile and the definition and listing of unacceptable HLA specificities. Sensitized patients where the antibody profile was not defined were disadvantaged in the allocation scheme by attracting fewer points.
Blood group identity between donor and recipient was required as a part of the 1998 NKAS, with limited exceptions for prioritized patients (tier 1, HSP; tiers 1 and 2, pediatric patients). One further exception was added after the introduction of the 1998 NKAS in that blood group O donor kidneys could be allocated to blood group B patients thereby trying to achieve equity between these two disadvantaged groups.
The allocation scheme was regularly monitored and reviewed by the Kidney Advisory Group of NHS Blood and Transplant. When considering refinements to allocation, as indicated by the review process, alternatives were evaluated using computer simulations based on data from the UK Transplant Registry database before implementation.
The 1998 NKAS was implemented in July 1998, and the impact of the scheme has been evaluated over the first 5 years. Initially, 43% of kidneys were allocated according to national rules (tiers 1 and 2), whereas the remainder were allocated to tier 3 patients according to local policy.
Impact on HLA Matching
In the 18 months before the 1998 NKAS was introduced, 7% of transplants in adult patients were 000 HLA-A, -B, and -DR mismatched, 43% favorably matched and 50% nonfavorably matched. In the first year of the scheme, HLA matching improved such that 13% transplants were 000 mismatched and only 38% nonfavorably matched (Fig. 2a). Although there was also an improvement for pediatric patients, HLA matching remained inferior to that achieved in adult patients.
When the 1998 NKAS was introduced, both kidneys from an adult donor were offered to 000 mismatched pediatric patients in tier 1, but only one kidney was offered to favorably matched patients in tier 2. To improve HLA matching of transplants in pediatric patients, the scheme was changed at the end of year 2, July 2000, and in subsequent years, both kidneys from a donor were offered for favorably matched children. As a result, HLA matchgrades for pediatric transplants improved to become comparable with those in adults (Fig. 2a).
The significant improvements in HLA matching for all adult and pediatric transplant patients over the three time periods (P<0.0001; Fig. 2a) were achieved through greater exchange of organs between transplant centers. In addition, there was increased access to favorably matched adult kidneys for pediatric patients: 49% of pediatric transplants used organs from adult donors in years 3 to 5 of the 1998 NKAS, compared with 40% in the first 2 years and only 22% in the 18 months of the previous allocation scheme.
HLA matching also significantly improved for regrafts in adults in the 5-year period: 28% of all regrafts were 000 mismatched compared with 16% in the last 18 months of the previous scheme.
HLA-DR Homozygous Patients
There was no priority for HLA-DR homozygous patients when the 1998 NKAS was first introduced. At the end of the first year, however, it was agreed that access to transplant for homozygous patients should be reviewed because of their longer waiting times and the excess of homozygous patients on the list compared with donors available. The excess was most apparent for HLA-DR homozygous patients with 22% of patients on the list homozygous at HLA-DR compared with 14% of donors.
Simulations showed that the degree of priority required could not be achieved by increasing the number of points assigned and that HLA-DR homozygous patients had to be prioritized in tiers 1 and 2 for 000 and favorably matched kidneys. The agreed change to the scheme (Fig. 1) was implemented at the end of the second year of the scheme in July 2000.
Analysis of the use of HLA-DR homozygous kidneys and the HLA matchgrades achieved in homozygous patients transplanted showed that after modification to the scheme, 44% of HLA-DR homozygous kidneys were transplanted into HLA-DR homozygous recipients compared with 26% previously (P<0.0001). The result was more transplants for HLA-DR homozygous patients and improved matchgrades of transplants performed. In the first 2 years, 11% of transplants in DR homozygous patients were 000 mismatched and 19% were favorably matched, whereas in years 3 to 5, 18% were 000 mismatched and 29% favorably matched (P<0.0001; Fig. 2b).
Equity of Access Across Blood Groups
At the end of the third year of the 1998 NKAS, a particular issue was identified with patients of blood groups O and B. Seven percent of transplant donors were blood group B and 50% blood group O, compared with 16% and 49% patients listed, respectively, giving rise to considerably longer waiting times for blood group B patients (Fig. 3). Reviewing these data, it was agreed that it would be appropriate to allocate some blood group O donor kidneys to blood group B patients to redress this imbalance.
Simulations predicted that if 000 and favorably matched adult blood group B patients were eligible to receive kidneys from blood group O donors, when there was no blood group O patient of otherwise equal priority, approximately 40 kidneys from blood group O donors would be allocated to blood group B patients per year, resulting in equivalent waiting times for blood group O and B patients within 5 years.
The change to the scheme was implemented at the end of year 4, in July 2002. In the subsequent year, 38 blood group B patients benefited from the revised rules, and the longer term effects in increasing equity to transplant are apparent in the reduced waiting times to transplant for subsequently registered patients (Fig. 3).
Transplantation of Highly Sensitized Patients
The transplant rate in HSP increased after the introduction of the 1998 NKAS. Approximately 50 HSPs were transplanted each year, compared with only 18 in the year before the introduction of the scheme. This resulted in a small reduction of HSPs on the waiting list from 500 (10.6%) in July 1998 to 468 (9.3%) by July 2003. One hundred fifty-six (62%) of the 251 transplants in HSPs were 000 mismatched.
Impact of the Points Score
For kidneys allocated nationally (43% of all kidneys in the first 2 years and 48% in the following 3 years), the points score was used to differentiate between patients of otherwise equal priority level in tiers 1 and 2 of the allocation scheme. In years 1 and 2 of the 1998 NKAS, 69% of national allocations required the use of recipient points score as a tiebreaker. In years 3 to 5, after the decision to give priority to HLA-DR homozygous patients by including further priority levels, the points score was only required in 58% of allocations. These factors were not influential in the allocation process and, therefore, had only a minimal effect in addressing inequity or promoting particular patient groups.
There was a small increase in the proportion of nationally allocated transplants for more difficult to match patients from 53% before the introduction of the scheme to 59% in the first 2 years (P=0.04), falling slightly to 57% in years 3 to 5 (P=0.14).
After introduction of the allocation scheme, there was a significant reduction in mean donor-recipient age difference among nationally allocated kidneys from 15.5 years (SD 11.6) to 13.3 years (SD 11.0) in the first 2 years and to 13.5 (SD 11.4) thereafter (P<0.0001).
Despite the early trend for transplanting younger patients in the scheme, when the mean age of transplant patients dropped from 45.3 years (SD 13.2) to 43.6 years (SD 12.6), there was no long-term effect on the age of patients transplanted (45.9 years [SD 12.9]).
Sensitization points had the desired effect of improving the reporting of antibody specificities and the accuracy of the virtual crossmatch performed within the algorithm and decreased the risk of positive crossmatch results and reallocation of kidneys. Although there was some evidence that the scheme was allocating kidneys to longer waiting patients than previously, this was limited in its effectiveness. The points for center “balance of exchange” kept the range of balances within acceptable limits.
Survival analyses were performed as part of the monitoring process to ensure that changes in allocation did not adversely affect graft outcome. Univariate survival estimates for all first kidney only grafts in adult patients are shown in Table 2. There was an improvement in 3-year death-censored graft (P<0.01) and patient outcomes (P=0.02) comparing transplants in the first 2 years of the scheme with those in the previous 18 months, with no change thereafter.
One of the primary aims of the 1998 NKAS for DHB donor kidneys was to improve the degree of HLA matching achieved on the basis that well-matched grafts have superior survival (5). Monitoring the impact of the allocation scheme over 5 years showed significant benefits in terms of achieving a well-matched cohort of transplants. In years 3 to 5 of the scheme, 16% of transplants in adults were 000 mismatched and a further 52% favorably matched, having a maximum of one HLA-A and -B locus specificity mismatched.
HLA matching is particularly important for pediatric patients not only to improve transplant outcome but also to avoid sensitization to HLA antigens, which may limit prospects for retransplant (7). In the early period of the 1998 NKAS, HLA matching improved for pediatric patients, but remained inferior to that achieved for adult recipients. After the scheme was modified to give pediatric patients increased access to adult kidneys, the level of matching reached that seen for adults for the first time in the United Kingdom.
Access to a large donor pool is crucial to find suitable crossmatch negative organs for HSPs. Eurotransplant has successfully run their acceptable mismatch scheme, whereby following definition of the antibody profile and identification of HLA specificities to which the patient has not made antibodies, patients are prioritized for virtual crossmatch negative organs (8). The 1998 NKAS benefited HSPs by affording them high priority for 000 mismatched kidneys, while identifying potential favorably matched kidneys for HSPs for whom the antibody profile was defined.
Regular review of the impact of the 1998 NKAS gave rise to revisions after its implementation, which significantly increased the number and degree of matching of transplants in homozygous patients and gave greater equity of access to transplant for patients of different blood groups.
The 1998 NKAS succeeded in achieving a cohort of well-matched transplants in the United Kingdom through mandatory sharing of at least one kidney from each donor. A weakness of the scheme, which became apparent over time, was that allocation of one kidney according to locally agreed criteria and to a local waiting list compromising patients from one to five transplant centers can contribute to inequity because of different regional imbalances in the availability of organs and the demand for transplantation. For example, there are large regional differences in the ethnicity of the population, which influence demand for transplantation and the supply of organs for transplant (9). Local allocation may also lack transparency and contribute to variation in waiting times for transplant between centers. For adult patients joining the list between 1997 and 1999, the median waiting time in three of the 25 UK transplant centers was less than 1 year, whereas for patients in five centers, the median time to transplant was in excess of 3 years, including one center whose patients waited an average of 4.5 years.
At the time of implementing the 1998 NKAS, many individual centers felt that retaining one kidney from a local donor for transplant in a local patient according to local priorities was a strong incentive to promoting local donor rates. In addition, the flexibility available through a partly local scheme allows for allocation to clinically urgent patients, which are not identified or prioritized on a national basis. A move to allocation of all kidneys through a national scheme was discussed but was not considered the most appropriate way forward, particularly given that for many patients a well-matched kidney was unlikely to be identified, and the principal aim of the 1998 NKAS was to exchange kidneys between centers only to achieve well-matched transplants where possible.
Given that less than 50% of kidneys were allocated through the national scheme and that the scheme was hierarchical in nature, the influence of the six points scoring factors was generally limited. Donor-recipient age difference points had the greatest impact, successfully reducing the instances of large age differences between donor and recipient. The development and application of matchability points was in part successful in transplanting patients who are difficult to match, but its effectiveness was limited because the patient had to be well matched with the donor to receive a kidney through the national scheme.
This lack of influence of key factors due to the overriding priority afforded to well HLA-matched transplants contributed to inequities in access to transplant in this partly national allocation scheme. Although notable improvements were made in access to well-matched transplants, in particular for pediatric and HLA-DR homozygous patients, it was recognized that only a new NKAS could address fully the wider issues related to equity of access to transplant.
In conclusion, the 1998 NKAS represented a significant advance for the allocation of DHB donor kidneys in the United Kingdom and, while not addressing inequities in access to transplant, it did largely achieve the principal goal of improving HLA matching.