Increasing the opportunity of live kidney donation by matching for two- and three-way exchanges

BACKGROUND: To expand the opportunity for paired live donor kidney transplantation, computerized matching algorithms have been designed to identify maximal sets of compatible donor/recipient pairs from a registry of incompatible pairs submitted as candidates for transplantation. METHODS: Demographic data of patients who had been evaluated for live donor kidney transplantation but found to be incompatible with their potential donor (because of ABO blood group or positive crossmatch) were submitted for computer analysis and matching. Data included ABO and HLA types of donor and recipient, %PRA and specificity of recipient alloantibody, donor/recipient relationship, and the reason the donor was incompatible. The data set used for the initial simulation included 29 patients with one donor each and 16 patients with multiple donors for a total of 45 patients and 68 donor/patient pairs. In addition, a simulation based on OPTN/SRTR data was used to further assess the practical importance of multiple exchange combinations. RESULTS: If only exchanges involving two patient-donor pairs were allowed, a maximum of 8 patient-donor pairs in the data set could exchange kidneys. If three-way exchanges were also allowed, a maximum of 11 pairs could exchange kidneys. Simulations with OPTN/SRTR data demonstrate that the increase in the number of potential transplants if three-way exchanges are allowed is robust, and does not depend on the particular patients in our sample. CONCLUSIONS: A computerized matching protocol can be used to identify donor/recipient pairs from a registry of incompatible pairs who can potentially enter into donor exchanges that otherwise would not readily occur.     

Increasing the supply of kidneys for transplantation

Kidney transplantation confers a survival advantage for patients with end-stage renal disease (ESRD) when compared to dialysis and improves the quality of life in a cost-effective manner. Currently there are more than 60,000 patients on the U.S. waiting list for kidney transplantation. In 2004, 16,879 kidney transplants, including 880 simultaneous kidney and pancreas transplants, were performed in this country. Recent strategies for increasing the supply of kidneys hold promise, such as systematic programs designed to improve consent rates for deceased donor organ procurement. Efforts to increase donation after cardiac death (DCD) have been highly successful and now account for more than 5% of all deceased organ donors. Transplantation of kidneys from DCD donors yields 1-year graft and patient survival rates equivalent to kidneys from brain-dead donors. Expanded criteria donor (ECD) kidneys from donors > or = 60 years of age (or donors age 50-59 years with certain comorbidities) confer a survival benefit for end-stage renal disease (ESRD) patients compared to remaining on dialysis on the waiting list. The number of live donor kidney transplants, both from biologically related and unrelated donors, is increasing. Paired live donor kidney transplants provide yet another transplantation opportunity for ESRD patients with willing but incompatible (by ABO or direct antibody) living donors.     

Successful living donor renal transplantation despite ABO incompatibility and a positive crossmatch

Potential live kidney donors have been rejected when the prospective recipients are blood type or crossmatch incompatible. By utilizing plasmapheresis combined with intravenous immune globulin (PP/IVIg) prior to surgery, donor-specific antibodies against blood group or human leukocyte antigens (HLA) have been removed, thereby allowing successful renal transplantation. A 26-yr-old male with a panel reactive antibody level of 100% and repeated positive crossmatches against deceased donor kidney offers, including zero HLA mismatched donors, successfully underwent ABO-incompatible kidney transplantation from his HLA-identical but nevertheless crossmatch-incompatible sister. The initial anti-A blood group isoagglutinin titers were 128, 256, and 1024 at room temperature, 37 degrees C, and 37 degrees C anti-IgG enhanced, respectively. With an individualized PP/IVIg regimen based on donor-specific antibody titer, however, the relevant antibodies were adequately reduced and hyperacute rejection avoided. Subsequent antibody-mediated rejection, likely directed against a minor histocompatibility antigen, was diagnosed on postoperative day 7 and successfully treated. Neither ABO, or crossmatch incompatibility, or both in combination prohibit kidney transplantation.     

ABO-incompatible kidney transplantation

When a renal transplant candidate's only medically-acceptable living kidney donor is ABO incompatible, the most common practice is to place them on the deceased donor list. Over the past few years, the implementation of paired kidney donor exchange programs and the development of protocols to overcome the ABO blood group barrier have become much more successful and widespread. Here we review the therapeutic options for patients whose only living kidney donor is ABO incompatible, with a specific emphasis on the rationale for and the current outcomes of ABO incompatible living donor kidney transplantation.     

Kidney paired donation 2011

Patients with incompatible live donors have had to resort to the long wait on the deceased donor list. Now, through kidney paired donation, these incompatible pairs can enter a kidney exchange program where kidneys are "swapped" between incompatible pairs. This review highlights the evolution of kidney paired exchange and reviews the challenges and ethical considerations within a paired exchange system.     

Altruistic Donor Triggered Domino‐Paired Kidney Donation for Unsuccessful Couples from the Kidney‐Exchange Program

Between January 2000 and July 2009, 132 individuals inquired about altruistic kidney donation to strangers. These donors were willing to donate to genetically and emotionally unrelated patients. Some altruistic donors wished to donate to a specific person, but most wished to donate anonymously. In domino‐paired donation, the altruistic donor donates to the recipient of an incompatible couple; the donor of that couple (domino‐donor) donates to another couple or to the waiting list. In contrast to kidney‐exchange donation where bilateral matching of couples is required, recipient and donor matching are unlinked in domino‐paired donation. This facilitates matching for unsuccessful couples from the kidney‐exchange program where blood type O prevails in recipients and is under‐represented in donors. Fifty‐one altruistic donors (39%) donated their kidney and 35 domino‐donors were involved. There were 29 domino procedures, 24 with 1 altruistic donor and 1 domino‐donor, 5 with more domino‐donors. Eighty‐six transplantations were performed. Donor and recipient blood type distribution in the couples limited allocation to blood type non‐O waiting list patients. The success rate of domino‐paired donation is dependent on the composition of the pool of incompatible pairs, but it offers opportunities for difficult to match pairs that were unsuccessful in the kidney‐exchange program.     

Renal Transplantation Across HLA and ABO Antibody Barriers: Integrating Paired Donation into Desensitization Protocols

The field of desensitization and incompatible transplantation has made great gains over the past decade. There are now several options and effective therapies for many patients who face antibody barriers. Kidney paired donation (KPD) and desensitization have traditionally been considered competing strategies and patients have been offered one or the other without regard for the probability of a successful outcome. It is now possible to predict which donor/recipient phenotypes will benefit from each of these modalities. KPD should be favored among patients with immunologic phenotypes that are likely to match without prolonged waiting times. However, as many as 50% of patients with incompatible donors will fail to find a match in a KPD pool and many of these patients could be desensitized to their donor. Positive crossmatch and ABO incompatible transplantation has been accomplished in selective cases without the need for heavy immunosuppression or B‐cell ablative therapy. Patients who are both difficult‐to‐match due to broad sensitization and hard‐to‐desensitize because of strong donor reactivity can often be successfully transplanted through a combination of desensitization and KPD. Using these various modalities it is estimated that most patients with incompatible live donors can undergo successful renal transplantation.     

Kidney transplantation in highly sensitized patients: are there options to overcome a positive crossmatch?

Presensitization against a broad array of human leukocyte antigens (HLA) is associated with prolonged waiting times and inferior graft survival in kidney transplantation. Since the late 1960s, a positive lymphocytotoxic crossmatch has been considered a contraindication for kidney transplantation and solutions, such as enrollment of eligible patients in the Acceptable Mismatch Program of Eurotransplant and kidney paired donation in the case of living donor kidney transplantation, have been proposed to avoid this barrier. Alternatively, a positive crossmatch might not be considered as a contraindication for kidney transplantation and one can try to overcome this hurdle by desensitization. In principle, there are three different ways to overcome the crossmatch barrier by desensitization. The highly sensitized patient awaiting a cadaveric kidney transplant may be desensitized either immediately pretransplant when an organ is offered or in advance, during the time on the waiting list, to increase his chance of having a negative crossmatch at the time of transplantation. In the case of living donor kidney transplantation, the patient can be desensitized for days to weeks until the positive crossmatch with his intended living kidney donor becomes negative. “Heidelberg algorithm” is a combination of different measures, such as pretransplant risk estimation, good HLA match, inclusion of patients in the Eurotransplant Acceptable Mismatch program, and desensitization, which leads to timely transplantation and excellent survival rates in highly sensitized patients at a low rate of toxicity. We believe that all available options should be utilized in an integrated manner for the transplantation of kidney transplant recipients who are at a high risk of antibody-mediated rejection.     

The Dutch National Living Donor Kidney Exchange Program

The wait time for deceased-donor kidney transplantation has increased to 4-5 years in the Netherlands. Strategies to expand the donor pool include a living donor kidney exchange program. This makes it possible that patients who cannot directly receive a kidney from their intended living donor, due to ABO blood type incompatibility or a positive cross match, exchange donors in order to receive a compatible kidney. All Dutch kidney transplantation centers agreed on a common protocol. An independent organization is responsible for the allocation, cross matches are centrally performed and exchange takes place on an anonymous basis. Donors travel to the recipient centers. Surgical procedures are scheduled simultaneously. Sixty pairs participated within 1 year. For 9 of 29 ABO blood type incompatible and 17 of 31 cross match positive combinations, a compatible pair was found. Five times a cross match positive couple was matched to a blood type incompatible one, where the recipients were of blood type O. The living donor kidney exchange program is a successful approach that does not harm any of the candidates on the deceased donor kidney waitlist. For optimal results, both ABO blood type incompatible and cross match positive pairs should participate.     

An economic assessment of contemporary kidney transplant practice

Kidney transplantation is the optimal therapy for end‐stage renal disease, prolonging survival and reducing spending. Prior economic analyses of kidney transplantation, using Markov models, have generally assumed compatible, low‐risk donors. The economic implications of transplantation with high Kidney Donor Profile Index (KDPI) deceased donors, ABO incompatible living donors, and HLA incompatible living donors have not been assessed. The costs of transplantation and dialysis were compared with the use of discrete event simulation over a 10‐year period, with data from the United States Renal Data System, University HealthSystem Consortium, and literature review. Graft failure rates and expenditures were adjusted for donor characteristics. All transplantation options were associated with improved survival compared with dialysis (transplantation: 5.20‐6.34 quality‐adjusted life‐years [QALYs] vs dialysis: 4.03 QALYs). Living donor and low‐KDPI deceased donor transplantations were cost‐saving compared with dialysis, while transplantations using high‐KDPI deceased donor, ABO‐incompatible or HLA‐incompatible living donors were cost‐effective (<$100 000 per QALY). Predicted costs per QALY range from $39 939 for HLA‐compatible living donor transplantation to $80 486 for HLA‐incompatible donors compared with $72 476 for dialysis. In conclusion, kidney transplantation is cost‐effective across all donor types despite higher costs for marginal organs and innovative living donor practices.     

Single‐Center Kidney Paired Donation: The Methodist San Antonio Experience

Many potential kidney transplant recipients are unable to receive a live donor transplant due to crossmatch or blood type incompatibility. Kidney paired donation increases access to live donor transplantation but has been significantly underutilized. We established a kidney paired donation program including consented incompatible donor/recipient pairs as well as compatible pairs with older non‐human leukocyte antigen identical donors. Over a 3‐year period, a total of 134 paired donor transplants were performed, including 117 incompatible pairs and 17 compatible pairs. All transplants were done with negative flow cytometry crossmatches and five were done with desensitization combined with paired donation. Kidney paired donation transplants included two‐way and three‐way exchanges as well as three chains initiated by nondirected donors. Of the sensitized recipients transplanted by paired donation, 44% had calculated panel reactive antibody levels greater than 80%. Transplantation of females and prior transplant recipients was significantly higher with paired donation. Only three episodes of rejection occurred and no transplants were lost due to rejection. These data highlight the potential of kidney paired donation and suggest that all transplant centers should be actively engaged in paired donation to increase access to live donor transplantation.     

Lack of impact of human leukocyte antigen matching in living donor kidney transplantation: experience at Akdeniz University

Lack of expansion of the deceased donor supply has resulted in a severe shortage of organs worldwide. Spousal donors are one possible alternative organ source for patients on the kidney transplant waiting list. Despite human lymphocyte antigen (HLA) matching between recipients and unrelated donors being poor, the reported survival rates for these grafts, including spouses, are comparable to those for grafts from living related donors and higher than those for deceased donor kidneys. In 2000, our renal transplantation program began accepting living donor-recipient pairs with one or zero HLA matches. The purpose of this study was to assess this policy for accepting living unrelated donors. The 3-year graft survival rates for the transplants from living unrelated donors were similar to that for transplants from living related donors (log-rank = 0.078). The number of HLA mismatches did not significantly influence the survival rates for either of these groups of living donor transplants. Multivariate analysis revealed that dialysis duration (P = .057) and recipient age (P = .066) negatively influenced patient survival in living donor kidney transplantation. The graft and patient survival rates for the donor transplantations were higher than those for deceased donor transplantations. In light of these findings and considering the increasing problem of organ shortage, we conclude that living unrelated kidney transplantation should be performed, with strict guidelines. Spousal donation is the most favorable form of living unrelated renal transplantation.     

Four years of experience with the Australian kidney paired donation programme

New approaches to increase kidney transplantation rates through expansion of live donor kidney transplantation have become necessary due to ongoing shortage of deceased donor organs. These strategies include desensitization in antibody‐incompatible transplants to overcome the barrier of blood group incompatibility or human leucocyte antigen antibodies between recipient and donor and kidney paired donation (KPD) programmes. In KPD, a kidney transplant candidate with an incompatible live donor joins a registry of other incompatible pairs in order to find potentially compatible transplant solutions. To match the largest possible number of donor–recipient pairs while minimizing immunologic risk, KPD programmes use sophisticated algorithms to identify suitable matches with simultaneous two‐way or more complex multi‐way exchanges as well as including non‐directed anonymous donors to start a chain of compatible transplantations. Because of the significant immunologic barriers when fewer donor options are available, the optimal solution for difficult‐to‐match, highly sensitized patients is access to more potential donors using large multi‐centre or national KPD registries. This review focuses on the first 4 years of experience with the Australian multi‐centre KPD programme that was established in October 2010.     

A Comparison of Populations Served by Kidney Paired Donation and List Paired Donation

Options for utilizing live donor kidneys from those who are blood type incompatible or crossmatch positive with their intended recipients include kidney paired donation (KPD), list paired donation (LPD) and desensitization. KPD provides live donor kidneys for both recipients but requires a match to another incompatible pair, while LPD utilizes the deceased donor pool but is restricted by ethical and logistic concerns. We simulated patients and their potential donors to determine which recipients could receive a kidney through KPD and LPD. With smaller populations (100 pairs or fewer), more kidneys were matched through LPD, although the greatest benefit was derived from a combination of LPD and KPD. With increasing population sizes, more patients were matched through KPD, including almost all patients who would have been eligible for LPD. At population sizes predicted to be achieved by a national paired donation system, the role of LPD became minimal, with only 3.9% of pairs unmatched through KPD eligible for LPD. Considerable overlap was seen between the pairs unmatchable by KPD and those ineligible for LPD, namely less-demanded donors and hard-to-match recipients. For this population, the best option may be desensitization.     

Increasing access to kidney transplantation in countries with limited resources: The Indian experience with Kidney Paired Donation

According to the Indian chronic kidney disease registry, in 2010 only 2% of end stage kidney disease patients were managed with kidney transplantation, 37% were managed with dialysis and 61% were treated conservatively without renal replacement therapy. In countries like India, where a well‐organized deceased donor kidney transplantation program is not available, living donor kidney transplantation is the major source of organs for kidney transplantation. The most common reason to decline a donor for directed living donation is ABO incompatibility, which eliminates up to one third of the potential living donor pool. Because access to transplantation with human leukocyte antigen (HLA)‐desensitization protocols and ABO incompatible transplantation is very limited due to high costs and increased risk of infections from more intense immunosuppression, kidney paired donation (KPD) promises hope to a growing number of end stage kidney disease patients. KPD is a rapidly growing and cost‐effective living donor kidney transplantation strategy for patients who are incompatible with their healthy, willing living donor. In principle, KPD is feasible for any centre that performs living donor kidney transplantation. In transplant centres with a large living donor kidney transplantation program KPD does not require extra infrastructure, decreases waiting time, avoids transplant tourism and prevents commercial trafficking. Although KPD is still underutilized in India, it has been performed more frequently in recent times. To substantially increase donor pool and transplant rates, transplant centres should work together towards a national KPD program and frame a uniform acceptable allocation policy.     

Virtual Crossmatch Approach to Maximize Matching in Paired Kidney Donation

We developed and tested a new computer program to match maximal sets of incompatible live donor/recipient pairs from a national paired kidney donation (PKD) registry. Data of 32 incompatible pairs included ABO and 4 digit‐high‐resolution donor and recipient HLA antigens and recipient's HLA antibodies. Three test runs were compared, in which donors were excluded from matching to recipients with either donor‐specific antibodies (DSA) >8000MFI (mean fluorescent intensity) at low‐resolution (Run 1) or >8000MFI at high‐resolution (Run 2) or >2000MFI and high‐resolution (Run 3). Run 1 identified 22 703 possible combinations, with 20 pairs in the top ranked, Run 2 identified 24 113 combinations, with 19 pairs in the top ranked and Run 3 identified 8843 combinations, with 17 pairs in the top ranked. Review of DSA in Run 1 revealed that six recipients had DSA 2000–8000MFI causing a possible positive crossmatch resulting in breakdown of two 3‐way and three 2‐way chains. In Run 2, four recipients had DSA 2000–8000MFI, also potentially causing breakdown of three 2‐way chains. The more prudent approach of excluding from matching recipients with DSA with >2000MFI reduces the probability of matched pairs having a positive crossmatch without significantly decreasing the number of possible transplants.     

Effectiveness of different kidney exchange mechanisms to improve living donor transplantation in Chile

Introduction

Chile has a low cadaveric organ donation rate; at the same time, living donor transplantation activity is also low. The purpose of this study was to analyze the impact on the number and quality of transplants using various mechanisms for kidney exchange from living donors to patients on Chile's waiting list.

Methods

A computerized model was developed to simulate five options for living kidney donation: (1) direct donation; (2) direct donation plus pairwise and three-way exchanges; (3) pairwise exchange; (4) three-way exchange; and (5) allocation of donors based on the top trading cycles (TTC) mechanism. We calculated the projected number of transplantations, adjusting for the risk of a positive crossmatch, as well as the average quality in terms of the human leukocyte antigen (HLA) match.

Results

If all patients on the waiting list have a willing direct donor, 47.7% of patients will receive a transplant. Allowing for incompatible pairs or pairs with a positive crossmatch an exchange of kidneys, can increase the number to 51.8%. This figure rises to 60% or 61% for pairwise or three-way exchanges, respectively. Although TTC ensures that 55% of the patients could be transplanted, the graft quality is better with an average HLA match of 3.5 versus 1.25.

Conclusions

These results showed that kidney exchange mechanisms can increase the number of living donor transplantations by 4% and 13%.     

Comparison of time on the deceased donor kidney waitlist versus time on the kidney paired donation registry in the Australian program

In the Australian kidney paired donation (KPD) program matching is based on acceptable mismatches, whereas deceased donor waitlist (DDWL) patients are allocated kidneys based on HLA antigen matching rules. Herein, we compared waiting time for a KPD match to the waiting time on the DDWL and the occurrence of matching in the DDWL for patients who were registered in both programs. Data on first dialysis, matches on the DDWL, KPD program entry, matches and transplant dates were assessed in 26 KPD recipients of the Australian program. There were 22 recipients who were listed in the DDWL and received kidney transplants by KPD. Time on dialysis until KPD transplantation was 808 ± 646 days. Eleven patients had never been matched with a deceased donor (waiting time 345 ± 237 days) and 11 had been matched on average 3 ± 5 times (waiting time 1227 ± 615 days, P < 0.0001 vs. never matched), but did not progress to transplantation because of positive crossmatch or class II donor‐specific antibody. Mean time from registration in the KPD program until kidney transplantation was 153 ± 92 days (P < 0.0001 vs. DDWL). KPD allocation using the acceptable mismatch approach is effective in identifying suitable live donors for some recipients within a relatively short time‐frame.     

Living donor kidney transplantation in a global environment

Live donor kidney transplantation has become a widely sought treatment by patients with end-stage renal failure. As the outcome for the genetically and emotionally related live donor transplants is the same, this review considers live kidney transplantation from the broad scope of current international practice. Unrelated live donor transplantation can now be performed for incompatible donor recipient pairs via a simultaneous paired kidney donation. However, acceptance of the scientific data that an unrelated live donor transplant can now be performed successfully should not be misconstrued as an acceptance that an unrelated kidney may be purchased via a vendor sale. At a recent World Health Organization (WHO) conference of Middle East transplant professionals a statement of unequivocal opposition to commercialism was drafted. In the United States, the Institute of Medicine has recently published a significant report that affirms the legal prohibition of organ sales. These documents are in accord with the guiding principles of the WHO and the membership policy of The Transplantation Society. The person who gives consent to be a donor should be competent, willing to donate, free of coercion, medically and psychosocially suitable, and fully informed of the risks and benefits as a donor. With these principles established, the Amsterdam Forum has set forth a comprehensive list of medical criteria that is now used internationally in the evaluation of potential kidney donors. Guidelines of a psychosocial evaluation are also presented in this report for individuals who come forward through internet solicitation and other public appeals. It is now evident that the annual number of available deceased donors will not resolve the ongoing shortage of organs. Nevertheless, live donor kidney transplantation may not be the realistic final solution to an international public health epidemic of renal failure that is the result of an aging population of patients that have had inadequate preventive medical care.     

The Dutch algorithm for allocation in living donor kidney exchange

The shortage of kidneys from brain-dead donors for transplantation has made it necessary to look for alternatives. Living kidney donation is one possibility. However, because of ABO blood group incompatibility or immunological reasons, transplantation of kidneys from a living donor is not always possible. The seven Dutch kidney transplantation centers have developed a joint protocol for crossover, or paired donor exchange, kidney transplantation. To ensure a fair chance for all participating donor-recipient pairs, the Dutch Transplantation Foundation has developed an allocation algorithm to match compatible donor-recipient pairs. A crossover match is performed every 3 months. The computer program developed by the Dutch Transplantation Foundation to match compatible donor-recipient pairs calculates the match probability (MP) of every potential recipient. The MP takes into account the peak panel-reactive antibodies (%PRA) of the recipient, the incidence within the crossover donor population of (compatible) ABO blood group, and HLA unacceptables of the recipient. The potential recipient with the lowest MP, in other words, the recipient with the smallest chance of finding a compatible donor in the pool, is ranked first. Until now, three matches have been performed in the Netherlands. A total of 53 pairs from all seven Dutch transplantation centers have participated. For 22 of the pairs a compatible donor-recipient pair was found.