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

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1 American Journal of Transplantation 2012; 12: Wiley Periodicals Inc. C Copyright 2012 The American Society of Transplantation and the American Society of Transplant Surgeons doi: /j x Single-Center Kidney Paired Donation: The Methodist San Antonio Experience A. W. Bingaman a, *,F.H.WrightJr. a, M. Kapturczak a, L. Shen a,s.vick a and C. L. Murphey b a Methodist Specialty and Transplant Hospital, San Antonio, TX b Southwest Immunodiagnostics Inc., San Antonio, TX *Corresponding author: Adam W. Bingaman, adam.bingaman@mhshealth.com 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. Key words: Anti-HLA antibodies, desensitization, paired kidney donation, sensitized patients Abbreviations: KPD, kidney paired donation; HLA, human leukocyte antigen; cpra, calculated panel reactive antibody; DSA, donor specific antibody; MFI, mean fluorescence intensity; UNOS, United Network for Organ Sharing. Received 08 October 2011, revised 25 February 2012 and accepted for publication 01 March 2012 Introduction The kidney transplant waiting list has continued to grow due to a limited supply of deceased donor organs and an increasing number of patients with end-stage renal disease. Live donor transplantation is a favorable option for patients with acceptable donors since recipients can avoid long wait times on dialysis and outcomes for live donor transplantation are better compared to deceased donor transplantation (1, 2). In order to receive a live donor kidney transplant, the recipient must be immunologically compatible with the donor. Compatibility testing includes blood typing (ABO) as well as histocompatibility testing. It is estimated that there are at least 6000 patients on the current kidney transplant waiting list with willing healthy donors who are not compatible (3). Desensitization and kidney paired donation (KPD) are options for patients to achieve a transplant with incompatible living donors. However, desensitization techniques are expensive, may be associated with higher patient morbidity and long-term outcomes are inferior making KPD to achieve compatible transplantation the preferred option (4 6). Computer modeling suggests that KPD is underutilized despite lower costs and better outcomes compared with desensitization (7 9). Since KPD was initiated in the United States, more than 1000 KPD transplants have been performed (10 12). Johns Hopkins initiated the first large single-center KPD program in 2000 and reported their 100th KPD transplant in December 2009 (13). Between January 2004 and December 2008, the Dutch national KPD program registered 312 incompatible pairs and performed 131 exchange transplants, making the Netherlands experience the most successful national program to date (14 20). Some transplant centers in the United States have elected to enter incompatible donor/recipient pairs into databases managed by KPD networks or alliances. UNOS has recently initiated an optional national program for KPD. The effectiveness and efficiency of these multicenter KPD programs or of a national program to significantly expand KPD transplants remain unclear. A single-center KPD program was established at Methodist Specialty and Transplant Hospital and the first KPD transplant was done in March We report here our initial 3-year experience with KPD. To our knowledge, our program has grown to become the largest single-center KPD program in the world. Two-way and three-way exchanges 2125

2 Bingaman et al. and chain transplants have been done and KPD has been combined with desensitization for selected highly sensitized patients. Compatible pairs with unfavorable donor recipient age matches have also been utilized. We show that KPD transplants significantly improve access to transplantation for disadvantaged groups including highly sensitized patients, females and retransplant patients with excellent outcomes and very low rejection rates. These results support expansion of KPD programs to enhance live donor transplant rates for patients with incompatible donors. Methods Patients This is an institutional review board approved study of patients consented to participate in the KPD transplant program at Methodist Specialty and Transplant Hospital in San Antonio, Texas. Written informed consent was obtained from all study participants. Consented incompatible pairs were entered into the KPD database daily and weekly meetings were held to review transplant possibilities. All patients with compatible, non-hla identical donors older than 45 years of age were also approached for participation in the KPD program. Recipient candidates with compatible donors were offered a younger kidney donor and were not asked to delay transplant once their compatible donor had been approved for donation. Thus, if an exchange had not been arranged for the compatible pair at the time both the donor and recipient were approved, then the compatible pair would be transplanted without an exchange. Histocompatibility management HLA typing, antibody identification and compatibility testing All patients and donors were HLA typed by DNA-SSO for HLA A, B, Cw, DR, DQA, DQB, DRw and if necessary for DP. Initially, patients were screened for HLA class I and II antibody using FlowPRA TM screen beads. Positive samples were further tested for HLA specificity using the Luminex platform and single antigen beads. Unacceptable antigens were assigned based on a multitiered algorithm. Specificities that fell between 1500 and 2000 mean fluorescence intensity (MFI) were not assigned as unacceptable but were flagged as antibodies that could cause weakly positive crossmatches. HLA antibodies greater than 2000 were assigned depending upon the sensitization level of the patient. Antibodies to C locus antigens were not assigned for highly sensitized recipient candidates because of lower surface expression levels of C locus antigens (21,22). Single antigen beads were performed every 6 months or when indicated (i.e. a recipient/donor crossmatch was unpredictably positive, a sensitizing event occurred, etc.). Crossmatches were performed by flow cytometry using monoclonal antibodies against CD3 to identify T cells and CD19 to identify B cells. Crossmatch cut-offs were established statistically and the standard cut-off used for this time period was >77 MCF for T cells and >110 MCF for B cells. An antihuman IgG specific secondary antibody was used to detect bound antigen/antibody complexes. Samples were acquired and analyzed on a Becton Dickinson FACS Canto II. KPD database A Microsoft Access database designed by Inessa Kaplan at Johns Hopkins University was obtained with permission and used for donor/recipient pairing (23). Patient HLA types and unacceptable antigens were entered into the database as well as demographic information to aid in age matching pairs. All consented potential donors for each recipient candidate were entered into the donor section of the database and included demographic information, ABO blood group and HLA typing. Match runs could be generated for all patients in the database or individually for each patient. The matching algorithm was first stratified by ABO compatibility and then by HLA compatibility. KPD transplants were arranged, based on the authors judgments, to provide benefit for the maximum number of recipients, the most highly sensitized recipients and recipients who had waited the longest in the KPD database. Consideration was also given to age and size matching of pairs. If multiple different KPD options were available, highly sensitized patients and patients with longer waiting times received priority. The current database does not allow blood type A subtypes to be entered and therefore all donors that were blood type A 2 subtypes were entered as blood type O. This notation required close oversight beyond the matching software program and independent blood type verification is required by two separate individuals prior to transplant. Any potential recipient for a blood type A 2 donor that was HLA compatible had an anti-a titer performed. Patients with anti-a titers less than 1:8 were considered to be compatible (24). Immunosuppression All KPD recipients were given a single dose of alemtuzumab for induction therapy and tacrolimus and mycophenolate mofetil for maintenance immunosuppression. Recipients who had been on steroids prior to transplant were continued on low dose prednisone posttransplant. In addition, selected highly sensitized patients and all desensitization patients were continued on low dose prednisone. Desensitization patients were treated with plasmapheresis and intravenous immune globulin (100 mg/kg) pretransplant to convert the flow cytometry crossmatch to negative. Results The KPD database Potential recipients were consented for entrance into the KPD database when confirmed as eligible transplant candidates at the initial evaluation without regard to the knowledge of potential donors. Potential donors underwent a comprehensive health screen to confirm they were candidates for donation prior to having blood drawn for compatibility testing. All potential donors received education about KPD and consented pairs were entered into the exchange database. Donors were not fully evaluated until a match was found and no donors with hypertension were used. If candidates received a transplant, lost their live donor(s) (due to health reasons or other), or became ineligible for transplant, they were removed from the database. From the initiation of the program in November 2007 through February 2011, a total of 160 recipient candidates with 272 potential donors remained in the KPD database. As expected, the majority of the recipient candidates remaining in the database were blood type O (67%), followed by A (21%), B (11%) and AB (1%) (Figure 1A). Interestingly, the largest percentage of donors remaining in our database were blood type O or A 2 (42%) followed by A 1 (39%), B (16%) and AB (3%) (Figure 1B). This high percentage of blood type O donors in the database reflects the highly sensitized recipient candidate population. Most 2126 American Journal of Transplantation 2012; 12:

3 Initiation of a Single-Center KPD Program with calculated panel reactive antibody (cpra) > 90% (Figure 2B). Of note, there are currently no patients with cpra < 40% in the database since all of these patients were expediently transplanted by KPD. Characteristics and outcomes of KPD transplant recipients Approximately 4 months after initiation of entries into the database, the first paired donor transplants were done. In next 3 years, a total of 134 KPD transplants were done, including 114 incompatible pairs and 17 compatible pairs done completely within our center and three other incompatible pairs coordinated by our program from outside centers. Of the 117 KPD transplants (excluding the 17 compatible pairs), 112 were done without desensitization and five were done in combination with desensitization (Figure 3A). Recipients ranged from preemptive transplantation to a maximum of 13 years on the wait list. The median time from reporting of the incompatible result to donor candidates until KPD transplantation was 4.5 months, ranging 1 18 months. Figure 1: Blood types in KPD database. (A) Blood type distribution of recipient candidates remaining in the database. (B) Blood type distribution of donor candidates remaining in the database. recipient candidates in the database were crossmatch incompatible with their original donors (58%), while 42% were blood type incompatible with their donors (Figure 2A). Of the crossmatch incompatible recipient candidates in the database the majority were very highly sensitized Of the five recipients who were desensitized, their cpras were 77%, 95%, 95%, 98% and 100%. Of note, the recipient with 77% cpra had significant C locus antibody which is not currently included in the cpra calculation, and thus all five of these patients were very highly sensitized and unlikely to ever be transplanted in the complete absence of donor-specific antibody (DSA). Figure 2: Reason for recipient candidate incompatibility in KPD database. (A) The distribution of blood type incompatible versus crossmatch incompatible pairs in the KPD database. (B) The distribution of cpras within the group of crossmatch incompatible recipient candidates in the database. Figure 3: KPD transplant recipients. (A) Distribution of KPD recipients transplanted with and without desensitization. (B) Modality of KPD by which recipients were transplanted. (C) Reason for recipient incompatibility with the original donor. The arrow on the left points to the blood type incompatibilities of the original pairs. The arrow on the right points to the cpras of the sensitized KPD recipients. The compatible pairs were excluded from this analysis. American Journal of Transplantation 2012; 12:

4 Bingaman et al. Figure 3: Continued If an acceptable nondirected donor was available to initiate a chain, then a one-way matching algorithm was used to plan KPD transplants. If a nondirected donor was not available, two- and three-way matching algorithms were used. Of the KPD transplants done, 36% were two-way exchanges, 36% were three-way exchanges and 28% were chain transplants initiated by three different nondirected donors (Figure 3B). The three separate transplant chains involved a five recipient exchange that ended in donation to a highly sensitized recipient at the top of the deceased donor waiting list, a 23 recipient exchange with a blood type O bridge donor and a nine recipient exchange with a blood type A 1 bridge donor. Both bridge donors plan to donate in the future to resume their respective chains. All recipients had negative T and B flow cytometry crossmatches at the time of transplant. The majority of KPD recipients (63%) were sensitized and crossmatch incompatible with their original donor, while 37% were ABO incompatible with their original donor (Figure 3C). Interestingly, the minority (13%) of transplanted sensitized patients had low levels of sensitization with a cpra < 40%. Presumably, most patients with low antibody levels had compatible donors. While 42% of transplanted sensitized patients had moderate levels of antibody (cpra 40 80%) a significant fraction (44%) were very highly sensitized with cpra > 80%. Notably, 24% of sensitized KPD recipients had cpra > 90%. Of the patients transplanted, 18 had antibodies to HLA C, eight patients had antibody to DP and two patients had antibody to DQ alpha and thus levels of sensitization were underestimated by cpra in many of our patients. Two traditionally disadvantaged cohorts of patients in transplantation are multiparous females and previously transplanted individuals due to the frequent formation of anti- HLA antibodies resulting from these sensitizing events. Thus, it is not surprising that these subgroups of high PRA patients may be over-represented in a database of incompatible pairs and thus may derive significant benefit from KPD. Indeed, within our KPD database, 61% of recipient candidates are female and 32% have had a previous transplant. We compared the frequency of live donor transplantation for females and retransplant patients within the KPD program with the frequency transplanted within our regular live donor program (Figure 4). Consistent with national data (10), females comprised 35% of our live donor recipients within the regular transplant program during the study period, whereas a significantly higher proportion of Figure 4: KPD increases transplantation of disadvantaged populations. (A) Comparison of female recipients of live donor kidney transplants during the study period within the regular live donor (LD) program (120/341, 35%) and kidney paired donor (KPD) program (65/117, 56%). (B) Comparison of retransplant recipients of live donor kidney transplants during the study period within the regular live donor (LD) program (27/341, 7.9%) and kidney paired donor (KPD) program (33/117, 29%). p-values shown are derived from Fisher s exact test American Journal of Transplantation 2012; 12:

5 Initiation of a Single-Center KPD Program Figure 5: KPD transplants relative to total volume of live donor transplants. Graphs show the number of KPD transplants relative to the number of total live donor transplants for each of the 3 years during the study period. The percentage of KPD transplants as a whole at the end of each year is shown to the right of each graph. females were transplanted (56%) within the KPD program. Also consistent with national data (10), retransplant patients comprised 7.9% of our live donor recipients within the regular transplant program during the study period, whereas within the KPD program, 29% were retransplant patients, also significantly higher than within the regular living donor program. These data highlight the increased access to transplantation through KPD for these traditionally disadvantaged cohorts of patients. With a median follow-up of 12 months posttransplant, there was one episode of cellular rejection which occurred 9 months posttransplant as a result of low-tacrolimus levels, one episode of early monocyte rich rejection and one episode of early antibody mediated rejection in a patient with a negative crossmatch and low-level DSA pretransplant who had not been desensitized. The median creatinine at both 6 months and 1 year after transplant were 1.3 mg/dl. No allografts were lost to rejection during the study period. Two recipients died with well-functioning allografts and one recipient experienced early graft thrombosis and graft loss. Potential and sustainability of KPD The success of a KPD program depends in large part upon the volume of incompatible pairs entered into the database. We have previously shown that our volume of KPD transplants increased substantially after approximately 100 recipient candidates had been added to our database (25). To determine the impact and potential of KPD to increase access to transplantation, we analyzed the volume of KPD transplants versus our overall volume of live donor transplants over the first 3 years of the KPD program (Figure 5). One year after initiation of the program, KPD transplants contributed 11% of the overall volume of live donor transplants. After 2 years, 27% of our live donor volume consisted of KPD transplants and after 3 years, 35% of our live donor volume consisted of KPD transplants. Thus, the volume and percentage of KPD transplants consistently increased over the 3 year time frame and substantially contributed to the growth of our live donor transplant program. These data also illustrate the sustainability of a single-center KPD program. Discussion Although awareness and acceptance of KPD has increased in the transplant community, the estimated potential has not been achieved. Here we report the initiation of a singlecenter KPD program which led to 134 KPD transplants over a 3-year time frame, including 71 in the final year of the study period. To our knowledge, this rapid growth and productivity of a single-center KPD program is unprecedented in the United States or elsewhere. Increased utilization of nondirected donors and of KPD combined with desensitization may further increase the number of possible transplants in the future. There are many challenges inherent in organizing and directing a successful KPD program. Importantly, significant additional resources to run and implement our KPD American Journal of Transplantation 2012; 12:

6 Bingaman et al. program were not necessary, with the exception of a significant time commitment by the clinical and HLA directors of the program. As our KPD volume increased, a full time nurse coordinator and scheduler were added to the transplant staff but no other dedicated support has been necessary. Some of the key features of our KPD program, listed in Table 1, have been central to the growth and success. While we do not feel that there are unique aspects of our patient population that have led to broad acceptance of KPD, we do feel that early and thorough education and consent of all recipient and donor pairs for entrance into the KPD program is essential. Retrospective attempts (weeks or months after incompatible test results) to consent incompatible pairs has proven to be time consuming and has led to lower rates of consent compared with prospective education. Solid-phase single antigen bead technology is utilized to obtain a comprehensive antibody profile of all sensitized patients to include identification of HLA A, B, C, DR, DRw, DQ and DP. Each recipient s profile is carefully reviewed and unacceptable antigens are assigned individually based on a multitiered MFI cutoff system that is correlated to crossmatch sensitivity and sensitization status of the patient. For example, recipient candidates who have low cpras are very likely to be transplanted by KPD in the complete absence of DSA and will thus have all unacceptable antigens assigned with an MFI greater than By contrast, recipient candidates with very high cpras are less likely to be transplanted by KPD in the complete absence of DSA and will have more conservative assignment of unacceptable antigens utilizing higher MFI cutoff values. Although we individualized the assignment of unacceptable antigens for each candidate, typically recipient candidates with cpra greater than 80% would only be assigned unacceptable class I and II antigens for MFI greater than Antibodies to HLA C antigens were not assigned because of lower surface expression levels of C locus antigens (21,22). We have found that flow cytometry crossmatches may be negative, or only weakly positive despite C antibody MFI levels greater than Using this flexible assignment Table 1: Key features of the Methodist San Antonio KPD Program Prospective education and consent of all donor and recipient candidates regarding KPD Comprehensive antibody analysis and HLA testing of all recipient and donor candidates Flexible assignment of unacceptable antigens into a computerized matching software program Combination of KPD with desensitization for selected highly sensitized recipients Storage of blood samples from all consenting donor candidates for future crossmatch testing Subtype all blood type A donors into A1 and A2 Use of compatible pairs of unacceptable antigens to assess level of risk affords our highly sensitized patients an opportunity to be crossmatched against realistic prospective donors as well as assigning definitive unacceptable antigens where indicated. While the absolute cut-off values of MFI used for assignment of unacceptable antigens would need to be established in each individual HLA laboratory, this multitiered approach for assignment of unacceptable antigens could be used by other transplant centers to identify patients that might do well with combined desensitization and KPD transplant. Once a potential match is identified by the computer database a flow cytometry crossmatch is performed to confirm compatibility. Early in the development of our program one of the obstacles encountered was obtaining blood from donors for crossmatching when a potential match had been identified. This process significantly delayed subsequent donor evaluations and impeded progress toward the transplant. We now obtain and store additional blood from all donors at the time of consent. Thus, when the computer database identifies a potential match, flow cytometry crossmatching can be done immediately to confirm compatibility. Importantly, our program does not initiate complete donor evaluations until a potential match has been identified. Therefore, significant effort and resources are not spent on pairs who are unlikely to find a match. Recipient candidates with cpra greater than 95% (or significant C, DQA or DP antibodies not included in the cpra calculation) that were unlikely to find a match in the absence of DSA were considered for combination KPD and desensitization. Each of the five patients transplanted with combination KPD/desensitization had flow cytometry crossmatches that were positive at a titer of 1:8 or less prior to desensitization. Pretransplant plasmapheresis and low dose IvIg (100 mg/kg) were given (three to five courses) and flow crossmatches were negative at 1:1 prior to transplant for all recipients. All blood type A donors are subtyped into A 1 and A 2 and all A 2 donors are classified as O in the database to allow them to possibly match with a non-a recipient with an anti-a titer less than 1:8 (24). In total, we utilized seven A 2 donors in seven separate exchanges who donated to non- A recipients with low anti-a titers, including four donors as part of three-way exchanges, two donors as part of twoway exchanges and one donor in a nine-way chain KPD. Thus, subtyping blood type A donors has had an important impact on our KPD program and should be considered by all KPD programs. In January 2009 we initiated a program to offer KPD transplantation to non-hla identical compatible pairs with donors over 45 years of age. During the study period, we utilized 17 compatible pairs to facilitate two-way, three-way and chain transplants. Because the compatible recipients with the older donors received younger kidneys, and the 2130 American Journal of Transplantation 2012; 12:

7 Initiation of a Single-Center KPD Program incompatible recipients were able to receive live donor transplants, both pairs may benefit from these KPD transplants (26,27). The median difference in age of the older compatible donor and the younger exchange donor in our 17 exchanges with compatible recipients was 25 years, range 5 42 year age difference, demonstrating this potential benefit in our series. With a large database of incompatible pairs, entrance of unsensitized recipients (especially with blood type O donors) into the KPD pool usually results in many potential matches. For example, unsensitized blood type A or B recipients with blood type O donors will always facilitate transplant for blood type O recipients who are incompatible with a younger blood type A or B donor. This strategy has been a key component to the growth of our program and should be considered more broadly by other KPD transplant programs. With a median follow-up of 12 months, we experienced a low acute rejection rate of 2.2%, despite transplantation of many highly sensitized and retransplant patients. We feel that this low rejection rate is due to several factors. It is clear that nonadherence is a significant risk factor for rejection (28,29), and our KPD patients have been extremely adherent with their medications and follow-up appointments. In addition, all recipients were given alemtuzumab which limits early rejection rates (30,31). Finally, all transplants were done with negative flow cytometry crossmatches (based upon standardized cutoff values set by the HLA laboratory) and only six recipients had donorspecific antibody at the time of transplant (one of whom had rejection). These data strongly suggest that high cpra or retransplant status, in the absence of DSA, may not be considered a significant risk factor for acute rejection. This is an important area for future study since such highly sensitized recipients may not need to be managed with higher levels of immune suppression. The national kidney transplant waiting list now includes nearly candidates with average waiting times of many years and with approximately 4500 deaths on the kidney waiting list each year (10). Thus, it is imperative that all centers consider all options for recipient candidates with acceptable healthy donors who are not immunologically compatible. At this time, there is broad disparity among transplant programs in the utilization of KPD and desensitization techniques to transplant patients with incompatible donors and many programs have little experience with either modality. Though desensitization has resulted in good short-term outcomes, it is becoming increasingly clear that long-term results are inferior compared with transplantation utilizing a compatible donor (32,33). Thus, we feel that the routine use of desensitization strategies by centers who do not participate in active KPD programs should be discouraged. Ideally, all recipient candidates with incompatible donors should first be considered for KPD transplantation and if a suitable exchange is not likely, only then be considered for desensitization. Mandatory reporting by transplant centers should be considered to include percentage of compatible live donor transplants, KPD transplants and desensitization transplants. In the United States, UNOS recently initiated a national pilot program for KPD, and thus we feel that the success of our single-center KPD program has important implications. Most strikingly, it highlights the potential of KPD to significantly increase the transplant rate of patients with incompatible donors. Indeed, over the last 12 months of the study period, 35% of our live donor transplants were KPD transplants. If this productivity could be replicated on a national level, it would result in nearly 2000 additional live donor transplants in the United States and a corresponding reduction in patients wait listed. Successful KPD programs in the United States have been achieved by single centers (12) as well as regional programs and alliances (34,35), however the relative value of these programs in relation to a single national program in increasing access to KPD is not yet known and is an important area for further investigation. Acknowledgments The authors would like to thank the entire staff of Methodist Specialty and Transplant Hospital that participates in the KPD program. We also thank the staff at Southwest Immunodiagnostics for all HLA laboratory support. Disclosure The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation. References 1. Andreoni KA, Brayman KL, Guidinger MK, Sommers CM, Sung RS. 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