As kidney paired donation (KPD) programs continue to grow and evolve (1–8), it is important to critically assess the efficacy of the various approaches to provide a basis for improvements. However, given the dynamic nature of these programs in which patients are being enrolled and others are being transplanted, uniform criteria for measuring the effectiveness of these programs are not clearly established.
In this study, we assessed the first 4 years of a three-site KPD program in which the primary goal was to provide an ABO compatible and negative or low-positive flow cytometric crossmatch kidney transplant to all recipients. In contrast to previous studies that focused more on structural and logistical issues involved in KPD (6, 7), we focused on the “performance” of our KPD program. The performance metrics that we were particularly interested in were the following: the number and characteristics of patients transplanted compared to those still waiting; the transplantation rates of groups identified as difficult to match, including highly sensitized and blood group O candidates; and the time to transplant for the recipients. Additionally, we wanted to identify the characteristics of donors that led to successful KPD transplants versus those that did not. Our initial experience highlights issues that are understudied in KPD and provides insights into possible improvements in our approach.
During the 40-month study period, 114 kidney transplant candidates were enrolled in the KPD program. The demographics of the cohort and reasons for entering into the program are listed in Table 1. The most common reason for entering the program was a +XM against the original donor (65/114; 57%). Forty-five candidates (39%) entered the program because of blood group incompatibility with the original donor. The remaining candidates entered the KPD program for viral serologic or significant age or size discrepancy, or both, between the original donor and the candidate.
During the study period, 90 transplants were performed as a result of the KPD program. These KPD transplants were accomplished with 13 scenarios involving two recipients (12 exchanges and 1 chain), four involving three recipients (three exchanges and one chain), five involving four recipients (one exchange and four chains), one involving five recipients (one chain), two involving six recipients (one exchange and one chain), one chain involving seven recipients, and one chain involving eight recipients. Ten never-ending altruistic donor chains were started with 10 nondirected donors. In all 10 scenarios, the end of the chain was identified from the outset and the last intended recipient was chosen from the deceased donor waiting list. When possible, all transplants were performed on the same operative day. In several cases, several days lapsed until completion of the chain because of logistical reasons. One bridge donor withdrew from the program for personal reasons. Twenty-three kidneys were shipped through commercial air between Arizona and Minnesota with a mean ischemic time of 678±80 min. Thus, 81 (71%) of the 114 candidates who entered into the KPD program received a transplant and 33 (29%) did not receive a transplant during the study period.
To perform the 81 transplants through KPD, we screened 368 potential donors. The average number of potential donors screened for each recipient was 3.9 (range 1–22). During this same time period, 538 patients underwent a “conventional” living donor kidney transplant. For these 538 recipients, 1,526 potential donors were screened (mean=2.8; range 1–120).
Patient and Graft Survival
Among the 90 transplants (including nine recipients from the deceased donor waiting list), 18 allografts experienced slow graft function, which was defined as serum creatinine decreasing less than 50% of baseline within the first 48 hr posttransplant. No patient required dialysis after the transplant, and all of these grafts achieved good graft function by 1 month. The estimated glomerular filtration rate of this group at 1 month posttransplant in this group was 54±16 mL/min/1.73 m2, which was similar to those patients who experienced immediate graft function (54±16; P=0.11). Five patients developed acute cellular rejection within the first year of the transplant and were treated successfully. One kidney was lost within the first week posttransplant because of renal artery thrombosis. The mean follow-up time for transplanted patients was 502±322 days (range 16–1,183 days). Actual 1-year graft survival was 98.2% and actual 1-year patient survival was 100%. No patient in the group still waiting for a transplant died or received a deceased donor kidney transplant during the study period. The average waiting time of the patients still waiting was 747±384 days, and all patients had been waiting at least 1 year (Table 1).
ABO Incompatible Candidates
Of the 45 candidates enrolled in the KPD program because of ABO blood group incompatibility with their originally intended donor, 37 (82%) received a transplant after an average waiting time of 164±108 days (range 15–420 days) (Table 2). Seventy-three percent of the transplanted ABOi patients were blood group O (average waiting time 179±110 days), whereas 11% were blood group B (average waiting time 168±149 days) and 17% were blood group A (average waiting time 94±46 days). Thirteen of these 37 recipients were sensitized with an average cPRA 30%±27% (range 2%–89%). At the end of the study period, only eight blood group O candidates were still waiting. They had waited for 760±290 days without a compatible donor match. Four of these eight patients were not allosensitized (cPRA=0%) and four were allosensitized with a mean cPRA of 95%±6% (range 84%–100%).
Positive Crossmatch KPD Patients
Sixty-five candidates entered the KPD program because of a positive crossmatch against their originally intended donor. Thirty-six patients (56%) received a transplant and 29 (44%) did not (Table 3). Of the 36 who underwent transplantation, 20 had a negative crossmatch against their donor and 16 had a low-level positive T- or B-cell, or both, flow cytometric crossmatch (channel shift >140, but <200). The crossmatch at the time of transplant with the KPD was lower than that of the crossmatch with their originally intended donor (Figure S1, SDC, http://links.lww.com/TP/A946).
The sensitized patients who received a transplant tended to have a lower cPRA than those who did not. The mean cPRA of the 36 transplant patients was 68%±24% (range=9%–99%) and the average waiting time was 195 days (60–632). In contrast, the sensitized patients who did not receive a transplant had an average cPRA of 96%±11% and had waited much longer (747±384 days, P<0.001).
Only four patients with a cPRA greater than 95% underwent transplantation during this period. The cPRAs of these four recipients were 99%, 97%, 97%, and 96%, respectively. These highly sensitized recipients waited longer than less sensitized recipients (mean waiting time=438 days, range=122–632 vs. 160 days, range=60–394 days; P<0.01). The four patients with a cPRA greater than 95% received kidneys from donors who were homozygous for at least three HLA loci (range 3–5). One of these recipients received a kidney with no mismatches at HLA A, B, DR, or DQ. Of the nine patients on the deceased donor waiting list who received living donor transplants to end KPD chains, eight had a cPRA of 0% and one had a cPRA of 56%. Four were blood group B, three were blood group A, and one each were blood group O and AB. Candidates were chosen from the deceased donor waiting list according to waiting time without priority for sensitization.
The Remaining KPD Waiting List
The number of patients listed and did not receive a transplant in the KPD program increased over time. As predicted by previous simulations, the KPD “waiting list” accumulated blood group O candidates and highly sensitized candidates (Fig. 1). All four ABOi candidates still waiting were blood group O and had been waiting for 760±290 days (Table 2). Of the 29 allosensitized candidates still waiting, 28 had a cPRA greater than 95% and had been waiting a mean of 724±397 days (Table 3; Fig. 1).
Using a cutoff of mean fluorescence intensity (MFI) less than 2,000 to determine an acceptable anti-HLA antibody during the study period, the transplantation rate for allosensitized candidates was 97% (34/35) for those with a cPRA less than 95% compared to 13% (4/30) for candidates with a cPRA greater than 95%. We explored the possibility that some of the remaining waitlisted sensitized candidates (n=29) might have a lower cPRA if a higher MFI cutoff was used (Fig. 2). We found that when the acceptable MFI was raised to 8,000, the average cPRA of the remaining sensitized candidates decreased to 85%. When an MFI of less than 10,000 was used, the average cPRA decreased to 55% and 83% (24/29) of the remaining +XM kidney transplants had a cPRA less than 95%. More importantly, when the acceptable MFI was raised to 10,000, 25 of the remaining sensitized patients now had a cPRA less than 75% (a level that commonly led to chains in KPD) and 24% (7/29) of these patients had a cPRA of 0% (Fig. 2). In contrast, increasing the MFI to 8,000 only resulted in nine candidates with a cPRA less than 90%. Because increasing the acceptable MFI will be associated with a more strongly positive crossmatch, patients who find paired donors through this modification would need to undergo desensitization before transplantation.
In this study, we assessed the first 4 years of a three-site KPD program integrated under the umbrella of a single institution. It is important to emphasize that our experience may differ significantly from KPD programs with different patient populations and with different approaches. Several aspects of our program likely affected the “performance” including (1) screening multiple donors for a single candidate, especially when they are highly sensitized; (2) allowing a weakly positive crossmatch in a pair when a negative crossmatch was not available; (3) requiring ABO blood group compatibility; (4) ending nondirected donor chains with donation to a candidate on the deceased donor waiting list rather than leaving the chain open-ended; and (5) a close, active interaction between three transplant programs with common protocols and a history of collaboration on many transplant issues. This unique relationship of three programs operating under a single institutional umbrella provides several advantages. First, the surgeons and nephrologists know one another well and practice in similar manners. Second, the protocols of the programs are developed with input from all three sites. Lastly, the financial structure of the institution eliminates obstacles to paired donation arising from questions of reimbursement.
We believe that this experience illustrates some of the important benefits of KPD and some of its limitations. As expected, KPD provided a kidney transplant with good outcomes for a large number of recipients in whom transplantation is otherwise difficult to perform. KPD also provided the benefits that living donation has over deceased donation, including shorter waiting time and lower rates of delayed graft function.
During the study period, we were able to perform transplantation in 77% of blood group O ABOi candidates and all other ABOi blood types. The mean waiting time from entering the KPD program to transplant for blood group O recipients was 164 days. This rate is encouraging and may be slightly better than that predicted by published simulations (9). The transplantation rate of blood group O recipients might be further enhanced if we modified our KPD algorithm to allow ABOi kidney transplantation (e.g., those with low anti-blood group antibodies) or if we approached ABO compatible, but mismatched living donor pairs to enter the KPD program (e.g., A recipients with O donors). Even when candidates have very high levels of blood group antibody or if transplant programs are unwilling or unable to perform ABOi kidney transplants, these candidates should remain in the KPD program because other incompatible recipients might enter the program and provide them with a blood group compatible donor. In the worst-case scenario, these nonsensitized candidates will eventually reach the top of the deceased donor blood group O list and receive a transplant. Lastly, subtyping of blood group A donors into A1 and A2 might allow them to match with a non-A recipient with an anti-A titer less than 1:8 without preconditioning.
From our experience with allosensitized patients in KPD, we believe that several important points have emerged. First, we were able to perform transplantation in 97% (34/35) of candidates with a cPRA less than 95% with either a negative crossmatch (56%) or with a weakly positive crossmatch without desensitization (44%). None of these patients developed acute AMR in the follow-up period. This transplantation rate appears to be slightly higher than that predicted by published simulations (9). From these data, we conclude that patients with a cPRA less than 95% are generally best served by waiting for a paired donor. In contrast, only 13% (4/30) of allosensitized candidates with a cPRA greater than 95% received a transplant. Thus, there was a steady accumulation of patients with a high cPRA, such that at the end of the study 90% of waiting candidates had a cPRA greater than 95%.
Comparing our KPD program’s performance to other programs is difficult. There is a relative paucity of detailed published data regarding the performance of most KPD programs, and different approaches to donor and recipient acceptance further complicate this issue. In the initial published experience of the National Kidney Registry, sensitized candidates comprised only 31% of the first 100 transplant recipients. Of the 72 remaining candidates, 46% had a cPRA greater than 80% (8). This report did not specifically address the most broadly sensitized candidates (cPRA >95%), but it does mirror the experience of KPD programs in Eurotransplant (10). Although these data and other reports (11) suggest that a larger, national KPD program might lead to a higher rate of transplantation compared to our three-site program, they also reinforce the concept that transplantation is difficult to perform in these highly sensitized patients even in larger programs.
We believe that these data suggest the continued need for desensitization protocols in these highly sensitized patients—especially those with a cPRA greater than 95%. Encouragingly, when we increased the MFI considered acceptable (e.g., up to 10,000, a level that is below our historical criteria for desensitization) in the patients who were still waiting in our KPD program, the vast majority showed a decrease in their cPRA to less than 90% and thus would be likely to find a paired donor. We would consider these patients to be capable of being “desensitized” with our existing plasma exchange and eculizumab regimen (12). Going forward, we would consider raising the acceptable MFI in patients with a cPRA greater than 95% who have been waiting for a period of time (e.g., >4 months) in the KPD program. As has been reported previously, combining desensitization with KPD is one method that could increase the number of transplants performed (13, 14).
In addition to screening a large number of donors and optimizing the use of nondirected donors (15), we suggest donors who are homozygous for several HLA loci are very useful for highly sensitized candidates. All four transplant patients who had a cPRA greater than 95% received kidneys from these types of donors. Perhaps the unique nature of these donors should be taken into consideration as KPD programs evolve to include compatible donors, and these donors could be preferentially allocated to highly sensitized candidates (16).
The ideal approach to KPD remains unclear. Important questions remain including the details of HLA and alloantibody testing, the prioritization of the various possible pairs, the use of open chains, the utility of large KPD programs versus tightly knit small ones, the logistics of screening many donors, and including compatible pairs. The exact role for desensitization also is unresolved, but data from studies such as this one are clarifying its role. An appropriate, ongoing assessment of the performance KPD programs is important to compare different approaches currently in use and new approaches that will emerge.
MATERIALS AND METHODS
This study describes our experience from the inception of our KPD program (August 2009–December 2012). The program includes the kidney transplant centers at Mayo Clinic Arizona, Mayo Clinic Florida, and Mayo Clinic Rochester. Kidney transplant candidates underwent a protocolized medical, surgical, and psychosocial evaluation according to the protocols at each of the three centers. Those candidates whose potential donor was ABO incompatible (ABOi) and those who had a positive crossmatch (+XM) against their potential donor were invited to participate in our three-site KPD program. After transplant candidate approval, donor evaluation began. For sensitized and blood group O candidates, we encouraged more than one donor to contact the center(s). Doing so allowed more potential donors to be entered into the computerized algorithm used to evaluate potential donor-recipient pairs. All potential donors underwent a brief telephone questionnaire to assess their candidacy for donation. Those who completed this initial screening satisfactorily were asked to have blood drawn for ABO typing, tissue typing, and crossmatching with the originally intended transplant candidate. Thus, we commonly screened more than one donor per candidate. The complete donor evaluation (e.g., visit to the transplant center, CT angiogram, etc.) was not performed on all donors, but rather was completed when the candidate only had one donor or if a donor was thought to be suitable for a possible paired donor chain. It is important to note that we have not to date approached otherwise compatible donor-recipient pairs for participation in the KPD program. Also, when a suitable nondirected donor came forward, he or she was encouraged to participate in the KPD program to maximize the number of transplants resulting from their donation.
KPD Program Protocol
The primary goals of our KPD program were to (1) avoid blood group incompatibility and (2) provide a negative crossmatch or a low flow cytometric (channel shift <200) +XM transplant. In certain cases, consideration was also given to age or size matching, or both, as well as viral (cytomegalovirus and Epstein-Barr virus) serologic status in otherwise HLA and ABO compatible pairs. Nondirected donors generally were utilized in chains that resulted in a donation to the deceased donor list rather than an open-ended and continuous chain.
Each center held recipient review conferences weekly and computerized algorithm was run after these conferences to identify potential donor-recipient pairs and chains of transplants. For the purposes of screening potential transplant combinations, unacceptable antigens were defined as those against which the candidate had a (MFI) of >2,000. Sensitized candidates did not receive priority when screening initially for potential combinations. The screening algorithm was intended to maximize the number of transplants generated from a potential chain. In the event of two or more chains resulting in the same number of transplants, priority was given to the most highly sensitized candidates. When potential transplant chains were identified, actual T- and B-cell flow cytometric crossmatches were performed. Recipients with a low-positive flow cytometric crossmatch did not undergo desensitization before the transplantation.
Antibody Characterization and other Clinical Assessments
Our approach to alloantibody testing has been described previously in detail (17). Screening of anti-HLA antibodies was performed with class I and class II HLA coated single antigen beads (LABScreen single antigen beads; One Lambda, Canoga Park, CA). This screening did not routinely include antibodies against HLA-DP.
Glomerular filtration rate was estimated using the Modification of Diet in Renal Disease study equation (18).
Results are expressed as means±standard deviation. Proportions of nominal data were tested using chi-square (Pearson) test. Continuous variables were tested using Student t test for parametric data and Wilcoxon test for nonparametric data; all tests were two-sided when applicable. Statistical analyses were performed using JMP statistical software system (SAS, Cary, NC). A P value of less than 0.05 was considered statistically significant.
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