253 CHAPTER 21 The National Kidney Registry: Transplant Chains – Beyond Paired Kidney Donation Jeffrey Vealea and Garet Hilb aUCLA Department of Surgery and bNational Kidney Registry, Los Angeles, California The advent of chain transplantation is one of the first time. Today, nearly half of living kidney the most exciting advancements to the field over donors are not biologically related to the recipient. CHAI the past 25 years. If transplant programs are able With improved media forms such as the internet, to make a paradigm shift and adopt new attitudes of the relationship between donor and recipient has N DONO cooperation rather than competition, this innovation been stretched to include members of the same has the potential to greatly expand the donor pool faith sanctuary, casual acquaintances or even with high quality living donor organs. unknown individuals. Kidneys from this latter group R Since facilitating its first transplants in 2008, of “altruistic”, “good Samaritan”, or the preferred E the National Kidney Registry (NKR) has become term “nondirected donors” (NDD), those without a X the most productive paired exchange system in the specific patient to whom the kidney is donated, are CHA world, with 62 transplants facilitated in 2009, over increasingly being utilized to trigger multiple chain NG 100 transplants facilitated to date and 200 trans- transplants (Fig. 1). plants forecasted for 2010. By working with leading The emergence of kidney exchanges is some- E - N transplant centers and leveraging cutting edge what vague. The idea that 2 living donor/recipient computer technology, the National Kidney Registry pairs could exchange kidneys to circumvent immu- ATI has broken through many of the barriers that have nologic incompatibility may have been developed ON stalled preceding paired exchange efforts. as early as 1970, however the first publication by A Felix Rapaport appeared in 1986 (2). On October K L EVOLUTION OF CHAIN 3, 2000 the first recorded US paired exchange I TRANSPLANTATION occurred at Rhode Island Hospital. The pairs DN EY Chain Transplantation is a byproduct of The Evolution of Paired Exchange RE “nondirected living donation” and “paired kidney Chains Traditional Paired Exchange G exchanges” which have independently evolved over ISTRY Non Directed time. Although living unrelated and nondirected Two Pair Exchange Altruistic Donor donor transplants had been reported since the R D D Cluster #1 1960’s, it wasn’t until the 1980’s that the opportunity R R D R to expand the living donor pool was appreciated R D (1). Until that point, the perceived low patient Three Pair Exchange D R and graft survival rates were felt to justify living Cluster #2 donation only from genetically related individuals D D D R D with at least one HLA haplotype in common. During R R R D R the 1990’s, kidney transplants between spouses Cluster R D #3 and “emotionally related” individuals markedly D Etc. increased. In 2001, the number of living donors exceeded the number of deceased donors for Figure 1. Variations on paired exchanges. Clinical Transplants 2009, Terasaki Foundation Laboratory, Los Angeles, California 254 VEALE AND HIL consisted of 2 offspring, each of whom wanted to ADVANTAGES OF CHAINS OVER donate to their corresponding mother but had blood TRADITIONAL PAIRED DONATION type incompatibilities (reciprocal A/B and B/A). This historic exchange was performed in sequence by Reciprocity Limits the Options in Dr. Paul Morrissey and Dr. Anthony Monaco with Paired Donation minimal media attention. One of the greatest advantages of chains over The first paired exchange program in the world traditional paired exchange is that chains do not rely was established in Korea in 1999. A year later, the on reciprocal matching. This enables each donor first paired exchange program in the US was started in the chain to be matched with the recipient that by Lloyd Ratner at Johns Hopkins. The Paired yields the longest or highest quality chain. This lack Donation Consortium was established by Steve of reciprocity facilitates more transplants and drives Woodle from the University of Cincinnati in 2002 superior matching performance. For example, the and was the first system to organize exchanges probability of finding a ABO match for a recipient between transplant programs in the United States. using traditional paired exchange (requiring a As other networks and paired exchange programs reciprocal match) is approximately 21% compared were initiated, new and more powerful matching to 46% for a recipient in a chain (Fig. 2). strategies began to emerge. Since there is no reliance on reciprocal match- In 2006, Montgomery, et al, proposed a varia- ing, the software for chains can be programmed to tion on traditional paired donation called “domino find superior age and HLA matches among ABO paired kidney donation” where a nondirected donor compatible patients and donors. In an unpublished was matched to a recipient who had a willing, but simulation study that utilized blood type and HLA incompatible living donor, in turn the incompatible data on 440 unrelated pairs from the UNOS Reg- donor agreed to give their kidney to the first compat- istry, the NKR chain matching program achieved a ible patient on the deceased donor waiting list (3). 50% zero HLA-A,-B,-DR antigen mismatch rate in This set the stage for Michael Rees to expand on the first 50 transplants (e.g. 25 of the 50 matches the “Domino Chain” approach by utilizing the incom- were HLA matched). This improved match quality patible donor as a “bridge donor” who could donate will lead to prolonged graft survival. Figure 3 sug- to another incompatible pair and continue a chain indefinitely, at least in principle. Rees subsequently Why Do Chains Find More Matches? and why are they higher quality matches? started the first “NEAD” (never ending altruistic donor) chain in 2007, facilitating 10 transplants over ABO PRA PROBABILITY a period of about a year (4). In practical applica- 65% x 70% = 46% tion, attempting to extend chains indefinitely was a D R suboptimal strategy as chains could quickly run out Give To of compatible pairs. This lead to broken chains as bridge donors waited long periods of time to donate and continue the chain. In 2009 the National Kidney Registry began facilitating hybrid chains by dynami- ABO PRA PROBABILITY 65% x 70% = 46% cally applying Domino and NEAD approaches to specific segments within a chain thereby balancing chain capacity to pool size in real-time. This mini- R Get Back D mized the chance of broken chains and reduced or eliminated bridge donor wait times, allowing for more GIVE TO GET BACK MATCH PROBABILITY transplants. These additional transplants included 46% x 46% = 21% some recipients on the deceased donor wait list who received living donor kidneys when chains were Figure 2. Probability of compatibility by reciprocal paired donation. systematically terminated. 255 Graft Half Life Donor Withdrawal The point in time when exactly 50% of kidneys are still functioning Deceased Donor Kidneys Donor Recipient 30 Living Donor Kidneys 28.0 NDD Donor Recipient 20 17.8 Years 14.2 D1 R1 D1 R1 10.5 10 D2 R2 R2 0 D2 Standard Standard Living Living Criteria Criteria Donors Donors Donors Donors 0-5 6 0-5 6 Antigen Antigen Antigen Antigen D3 R3 CHAI Match Match Match Match Figure 4. Impact of donor withdrawal on paired Antigen Match Benefit N DONO 5 year graft survival rates donation. 77.2% 74.9% 75.0% simulataneously. The fact that transplantations are 72.2% performed simultaneously during paired exchanges 68.2% Graph 65.6% 66.7% places a tremendous burden on hospitals, operat- R Survival E ing rooms, surgeons, nurses, support staff and Rate X CHA Zero One Two Three Four Five Six the patients. For example, a simultaneous 3-way Donor Recipient Antigen Match paired exchange requires 3 donor surgeons (likely Source: Based on OPTN data as of June 13, 2008 laparoscopically trained), 3 recipient surgeons and NG Figure 3. Benefits of better HLA matching. 6 operating rooms. Very few transplant programs E - N gests that the expected half-life of an HLA-matched in the country can field the surgeons and operating living donor kidney could be as high as 28 years rooms to support this requirement. Conversely, a ATI small center with one donor and recipient surgeon compared to 18 years for one that is completely ON mismatched (5). Better matching will therefore could complete a chain involving the same 6 pa- tients quite easily. The altruistic donor could donate A reduce the competition for organs on the waiting K L list as many recipients currently return to the wait to the first recipient on one day, the recipient’s I list after their first transplant fails. To underscore original incompatible donor could then donate to DN the significance of this, 19% of candidates on the the second recipient the following day (or following EY week, to help their “loved one” who just received deceased donor waiting list have already had one RE transplant (http://www.optn.org). a transplant recover) and so forth. The logistical simplicity of chains levels the playing field and does G ISTRY Chains Improve Transplant Logistics not advantage larger programs when organizing exchanges. Traditional paired exchange transplants are performed simultaneously to eliminate the pos- THE NKR APPROACH sibility of donors withdrawing and creating a situ- ation where a patient’s donor donates a kidney to During 2008, as the NKR was building a core of another pair and the patient does not get a kidney 10 transplant centers and establishing its approach in return. Chain transplantation does not have such to facilitating transplants, 21 transplants were a risky downside. If a donor withdraws in a chain, completed (Fig.