Kidney transplantation in adults: Kidney paired donation

INTRODUCTION — The issue of whether a given potential living kidney donor is "compatible" with a designated recipient has been a key factor since the first successful living-donor kidney transplant between the Herrick identical twin brothers in 1954 [1]. Compatibility between individuals can have a variety of manifestations, but, in living-donor transplantation, it has come to relate to ABO or human leukocyte antigen (HLA) typing and crossmatching.

Approximately one in three potential living kidney donors is ABO incompatible or crossmatch positive with his or her intended recipient [2]. Such donors have been traditionally deemed "incompatible," irrespective of their motivation to donate and their health status. Two main strategies have been developed to overcome these barriers: desensitization and kidney paired donation (KPD; also known as paired kidney exchange). KPD is typically the exchange of kidneys between two or more ABO- or HLA-incompatible living donor-recipient pairs, such that recipients receive compatible kidneys. KPD was first employed in South Korea in the 1990s as an innovative response to a shortage of deceased-donor kidneys for transplantation [3]. The first KPD transplants in Europe and the United States were performed in 1999 [4] and 2000 [5], respectively.

The legality of KPD, with respect to the National Organ Transplant Act (NOTA) requirement that organs not be donated in return for "valuable consideration" (money or financial equivalents), was confirmed in the United States by the 2007 so-called "Norwood Amendment" to NOTA, which permitted the development of national KPD programs [6].

Alvin Roth and Lloyd Shapley were awarded the 2012 Nobel Prize in economic science for developing the complex algorithms that are required to match large numbers of donors and recipients in KPD. The underlying concepts also form the basis of the various medical residency and fellowship matching programs in use in the United States.

In 2019, there were 1118 KPD transplants in the United States, constituting approximately 16 percent of all living-donor transplants, and KPD is the only growing segment in living kidney donation [7]. A number of KPD programs are available, the largest being the National Kidney Registry (NKR). The development of a national KPD program has been considered [8]. Efficient KPD represents the pinnacle of institutional, programmatic, and professional cooperation for the benefit of recipients with living donors deemed "incompatible."

This topic will provide an overview of KPD. HLA sensitization and crossmatch testing as well as desensitization strategies for HLA- and ABO-incompatible transplantation are discussed separately:

●(See "Kidney transplantation in adults: Overview of HLA sensitization and crossmatch testing".)

●(See "Kidney transplantation in adults: HLA-incompatible transplantation".)

●(See "Kidney transplantation in adults: ABO-incompatible transplantation".)

TYPES OF KIDNEY PAIRED DONATION

Two-pair exchange — In its simplest form, KPD can be used as a solution for donor-recipient pairs with ABO or human leukocyte antigen (HLA) incompatibility. In this scheme, two or more incompatible donor-recipient pairs are matched to other pairs with complementary incompatibilities (ie, donor swap). As an example, a blood group A to B couple would be set up to exchange with a blood group B to A couple (figure 1).

Domino kidney paired donation — The addition of nondirected donors (donors who do not designate a specific recipient) triggered the next evolution of KPD. The concept incorporates a nondirected, anonymous living donor (sometimes referred to as an altruistic donor or Good Samaritan donor) with incompatible donor-recipient pairs. To achieve optimal benefit from the nondirected donor, the donated kidney is matched to a recipient who has an incompatible living donor. In turn, the recipient's incompatible living donor donates his or her kidney to the next incompatible pair (paying the generosity forward), generating a "domino" effect that ultimately terminates with a donation to a recipient on the deceased-donor waiting list [9] (figure 2).

Bridge donors forming chains of transplantation — If, instead of donating to the deceased-donor waiting list, the final donor waits until a suitable match is found with a new incompatible pair, they become a "bridge" donor and can generate "clusters" or "chains" of living-donor transplants. The number of surgical procedures involved in such chains mandates that they be nonsimultaneous and typically at different institutions, so-called nonsimultaneous, extended, altruistic donation (NEAD) chains [10].

The mean chain length triggered by a single nondirected donor is five transplants [11]. There has been concern that bridge donors might back out of donation or "renege" once their intended recipients have been transplanted, thereby breaking chains and causing distress in the paired recipient. Such reneging is unusual, and, when it occurs, it is typically due to medical and logistic issues rather than intentional exploitation [12].

Living-donor kidney shipping — In order to expand the KPD donor pool to enhance matching algorithms, kidney chains often utilize multiple institutions and nonsimultaneous surgical procedures. Transfer of kidneys over distance and time is common practice in deceased-organ donation but was considered "taboo" for living-organ donation. The first shipped living-donor kidney that was shipped "coast-to-coast" across the United States by commercial airline occurred in 2008; this sentinel event is responsible for the expansion of KPD. Prior to this, the donor traveled inconveniently to the hospital of the recipient, often away from cohabitating individuals, in an unfamiliar city [13].

Thousands of living-donor kidneys have been shipped, and the cold ischemia times that such shipping entails do not appear to have an unfavorable effect on outcomes [14]. Delayed graft function occurs in approximately 5 percent of cases irrespective of cold ischemia time and donor age. There is also no significant association between cold ischemia time and all-cause graft failure, death-censored graft failure, or mortality. (See 'Outcomes of kidney paired donation' below.)

Virtual crossmatches have also permitted more rapid assessment of potential donor-recipient pairs with an accuracy approaching 99 percent of a traditional crossmatch. The living-donor kidneys are packaged in a manner similar to kidneys from deceased donors and are fitted with a global positioning system (GPS) to prevent loss. (See "Kidney transplantation in adults: Overview of HLA sensitization and crossmatch testing", section on 'Virtual crossmatch'.)

Compatible pairs — A "compatible pair" refers to a recipient-donor combination where the ABO matching is compatible and crossmatching is negative. These pairs do not need to engage in KPD, since the donation can occur directly. Participation of compatible pairs within KPD creates additional transplant opportunities for incompatible pairs. The compatible pair may benefit by virtue of the recipient achieving a better "match" in terms of HLA, kidney size, or donor age, which may translate into better long-term transplant function [15].

An example might be a 60-year-old uncle who donates as part of KPD rather than donating directly to his compatible 20-year-old niece, so that the niece receives a kidney with a potentially longer functional life from a 30-year-old donor and a 65-year-old recipient may receive a well-matched kidney from the 60-year-old uncle.

Quasi-compatible pairs — A "quasi-compatible pair" refers to a recipient-donor combination in which the recipient may proceed to transplantation without desensitization or KPD but is at significantly increased risk for acute rejection and/or reduced kidney allograft survival if transplanted with the original intended donor. Such pairs are likely to also benefit from KPD. Examples of quasi-compatible pairs include the following [16]:

●Female recipients of a kidney from a spouse or a child with potential re-exposure to paternal antigen

●Recipients with reexposure to an HLA antigen from a previously rejected kidney transplant

●Recipients with a donor-specific antibody (DSA) and a negative or low-level flow cytometry crossmatch

●An A2 blood group donor to an O or B blood group recipient

●Donor-recipient pairs with a substantial difference in donor/recipient glomerular filtration rate (GFR)

●Donor-recipient pairs with substantial age differences

●Cytomegalovirus (CMV) or Epstein-Barr virus (EBV) seropositive donor to a seronegative recipient

Advanced donation and "voucher" for future kidney transplantation — Initially, KPD operative procedures occurred simultaneously or near simultaneously. To facilitate kidney-chain development, and to accommodate the convenience and time constraints of living donors, the living donation was sometimes performed weeks in advance of the recipient's procedure in so-called "out-of-sequence" or "advanced" donations [13]. Advanced donation may occur weeks or even months ahead of the recipient procedure [17].

"Vouchers" represent another evolution in KPD and exhibit two fundamental differences from standard advanced donations. First, the intended recipients (voucher holders) have chronic kidney disease (CKD) but are not yet in need of a kidney transplant. Second, voucher donors function similarly to nondirected donors and can trigger long chains of transplants as they do not have a paired recipient in the current chain [18]. The first voucher holder was a grandfather in his 60s who wanted to ensure that his young grandchild with CKD would receive a living-donor kidney when and if the need arose. The grandfather was concerned that, by that time, he would have "aged out" of being a donor. The voucher program hence resolves "chronologic incompatibility" between donor and recipient pairs [19]. To alleviate concerns that the voucher donor would lose the capacity to provide a kidney to healthy loved ones in the unlikely event that they would develop CKD, the National Kidney Registry (NKR) permits the voucher donor to designate up to five healthy individuals as kidney recipients [19]. Potential donors who did not donate may elect to donate by voucher to ensure that their intended recipient will receive a living-donor transplant in the event that the first transplant fails [20].

Concern that there might not be an adequate number of living-donor kidneys to fulfill the obligations of the vouchers has been addressed in a report that shows that in 90 percent of the projected 50-year simulations, the number of available donors exceeded the number of voucher redemptions by over sixfold [21].

In a report of the seven-year experience with voucher-based kidney donation, each donation sparked a chain with an average length of 2.3 downstream kidney transplants [22]. Nearly 20 percent of the over 570 transplants facilitated through voucher-based donations were in highly sensitized recipients. Voucher donors tended to be in their 40s, predominantly female, predominantly White, and over 40 percent had blood type O. It is suggested that this influx of donors has decreased the exchange waiting time in the respective registry by over three months. The time from voucher redemption to actual kidney transplant ranged from 36 to 155 days, with highly sensitized and difficult to match recipients on the longer end of that spectrum. All voucher redemptions produced timely kidney transplants.

WHEN TO CONSIDER KIDNEY PAIRED DONATION — KPD should be considered for all transplant candidates with a living donor who is medically able but cannot donate a kidney to the intended candidate because of ABO or human leukocyte antigen (HLA) incompatibility. In addition, KPD should be considered for compatible donor-recipient pairs if, through KPD, the recipient has the opportunity to receive a better-matched transplant in terms of HLA, kidney size, or donor age. (See 'Compatible pairs' above.)

Kidney paired donation versus desensitization — KPD and desensitization represent two techniques to overcome different forms of donor-recipient incompatibility [23]. They each have advantages and disadvantages that need to be weighed in advising recipients and their designated donors. KPD is bureaucratically complex, requiring matching algorithms, organ shipping, and coordination between transplant centers. Medically, the transplant procedures themselves are typically straightforward. Desensitization, on the other hand, is bureaucratically straightforward but medically complex, requiring sophisticated crossmatching (for ABO and HLA antibodies) and the use of plasmapheresis, intravenous immune globulin (IVIG), and other agents. An approach to determining the need for KPD versus desensitization in HLA-sensitized patients is discussed in more detail elsewhere. (See "Kidney transplantation in adults: HLA-incompatible transplantation", section on 'Approach to the sensitized transplant candidate'.)

KPD and desensitization can work together particularly for highly sensitized patients. KPD can help to avoid strong donor-specific antibodies (DSAs), enabling desensitization to help manage weaker DSAs.

WHO CAN BE A DONOR? — The issue of incompatibility is a frequent concern of potential living donors and their designated recipients. KPD and desensitization permit the standard incompatibilities for ABO and human leukocyte antigen (HLA) to be overcome. Thus, in principle, any donor can be made compatible, directly or indirectly, if the donor is healthy, motivated, and can successfully complete the standard living-donor evaluation. Simplistically put, compatibility is the concern of the transplant center, while finding a healthy and motivated donor becomes the concern of the patient. (See "Kidney transplantation in adults: Evaluation of the living kidney donor candidate".)

OUTCOMES OF KIDNEY PAIRED DONATION — Patient and graft outcomes after KPD are at least comparable with, and may be better than, those after standard living-donor kidney transplantation [24-28]. The following studies illustrate the range of findings:

●In an analysis of 2037 consecutive KPD transplants performed between 2008 and 2017 through the National Kidney Registry (NKR), a voluntary KPD network, KPD transplant recipients had comparable one- and three-year graft survival rates and higher five-year graft survival rates compared with recipients of non-KPD living-donor kidney transplants within the same period [24].

●In a study of 240 KPD transplants performed in Canada between 2008 and 2013, patient and allograft survival rates were 99 and 96 percent, respectively, among recipients with at least one year of potential follow-up [26]. Biopsy-confirmed acute rejection and antibody-mediated rejection occurred in 8 and 3 percent of patients, respectively.

●A study linking the Scientific Registry of Transplant Recipients and the National Kidney Registry compared outcomes of traditional (originally incompatible) recipients with originally compatible recipients [28]. Of 154 compatible pairs, motivation for participation in paired exchange was predominantly to improve human leukocyte antigen (HLA) matching. Compared with the original compatible donor, actual donors were younger (39 versus 50 years), less often female (52 versus 68 percent), had a higher BMI (27 versus 25 kg/m²), were less frequently blood type O (36 versus 80 percent), and had higher eGFR (99 versus 94 mL/min/1.73 m²), with a better living kidney donor profile index score (median 7 versus 22). These changes, however, did not translate into a meaningful impact on overall graft outcomes and mortality.

KIDNEY PAIRED DONATION PROGRAMS — In the United States, there are several KPD programs available for enrolling incompatible donor-recipient pairs:

●National Kidney Registry (NKR)

●Alliance for Paired Kidney Donation

●United Network for Organ Sharing (UNOS) Kidney Paired Donation Pilot Program

Outside of the United States, KPD programs have also been established in Canada, the United Kingdom, the Netherlands, Spain, Israel, South Korea, and Australia.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Kidney transplantation".)

SUMMARY AND RECOMMENDATIONS

●Definition – Kidney paired donation (KPD; also known as paired kidney exchange) is the exchange of kidneys between two or more ABO- or HLA-incompatible living donor-recipient pairs, such that recipients receive compatible kidneys. (See 'Introduction' above.)

●Types of KPD

•Two-pair exchange – In its simplest form, KPD can be used as a solution for donor-recipient pairs with ABO or human leukocyte antigen (HLA) incompatibility. In this scheme, two or more incompatible donor-recipient pairs are matched to other pairs with complementary incompatibilities (ie, donor swap). (See 'Two-pair exchange' above.)

•Domino KPD – Domino KPD incorporates a nondirected, anonymous living donor with incompatible donor-recipient pairs. These individuals offer to generously donate a kidney but do not have an intended recipient. To achieve optimal benefit from the nondirected donor, the donated kidney is matched to a recipient who has an incompatible living donor. In turn, the recipient's incompatible living donor donates his or her kidney to the next incompatible pair, generating a "domino" effect that ultimately terminates with a donation to a recipient on the deceased-donor waiting list. If, instead of donating to the deceased-donor waiting list, the final donor waits until a suitable match is found with a new incompatible pair, they become a "bridge" donor and can generate "clusters" or "chains" of living-donor transplants. (See 'Domino kidney paired donation' above and 'Bridge donors forming chains of transplantation' above.)

•Compatible pairs – A "compatible pair" refers to a recipient-donor combination where the ABO matching is compatible and crossmatching is negative. These pairs do not need to engage in KPD, since the donation can occur directly; however, participation of compatible pairs within KPD creates additional transplant opportunities for incompatible pairs. The compatible pair may benefit by virtue of the recipient achieving a better "match" in terms of HLA, kidney size, or donor age, which may translate into better long-term transplant function. (See 'Compatible pairs' above.)

•Advanced donation and vouchers – Initially, KPD operative procedures occurred simultaneously or near simultaneously. To facilitate kidney-chain development, and to accommodate the convenience and time constraints of living donors, living donation can be performed weeks to months in advance of the recipient's procedure in so-called "out-of-sequence" or "advanced" donations. "Vouchers" represent another evolution in KPD and exhibit two fundamental differences from standard advanced donations. First, the intended recipients (voucher holders) are not yet in need of a kidney transplant and may never need a kidney transplant. Second, voucher donors function similarly to nondirected donors and can trigger long chains of transplants as they do not have a paired recipient in the current chain. (See 'Advanced donation and "voucher" for future kidney transplantation' above.)

●When to consider KPD – KPD should be considered for all transplant candidates with a living donor who is medically able but cannot donate a kidney to the intended candidate because of ABO or HLA incompatibility. In addition, KPD should be considered for compatible donor-recipient pairs if, through KPD, the recipient has the opportunity to receive a better-matched transplant in terms of HLA, kidney size, or donor age. (See 'When to consider kidney paired donation' above.)

●Outcomes of KPD – Patient and graft outcomes after KPD are at least comparable with, and may be better than, those after standard living-donor kidney transplantation. (See 'Outcomes of kidney paired donation' above.)