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Abstract

French

Background:

Kidney transplantation is the best treatment for chronic kidney failure, but antibody-mediated rejection (AMR) is a major cause of kidney transplant loss. Human leukocyte antigen (HLA) molecular-compatibility-based organ allocation aims to reduce the risk of donor-specific antibody formation and thereby lower the risk of AMR. However, integrating molecular compatibility in organ allocation could introduce barriers to access, consequently raising ethical concerns.

Objective:

The objective of this study was to gather perspectives of HLA professionals on molecular matching in kidney transplantation.

Design:

Individual semi-structured interviews.

Setting:

Canadian HLA laboratories.

Participants:

HLA laboratory directors or HLA professionals.

Methods:

Seven participants took part in semi-structured interviews between January and June 2024. The interviews were digitally recorded, transcribed, and analyzed using the qualitative description approach.

Results:

Participants reported positive feelings regarding the current allocation system but highlighted that HLA matching could be improved. They differed on whether kidney allocation should prioritize medical utility or fairness. While acknowledging the potential benefits of precision medicine in improving transplant outcomes, experts emphasized that its implementation confronts both scientific uncertainties and practical challenges, identifying logistical, financial, technological, and occupational barriers. They expressed concerns regarding decreased access to kidney transplantation for marginalized groups, recommending the adoption of mitigation measures. Regarding the kidney-paired donation program, experts supported integrating molecular matching as an optimizing tool to complement the current algorithm. Participants recommended that future implementation of molecular matching in Canada should involve nationwide collaboration, establishing a maximum wait time and appropriate selection criteria, additional research, adequate staffing and funding for HLA laboratories, as well as education of transplant professionals and patients.

Limitations:

The major limitation of this study is the small number of participants, all of whom were Canadian HLA professionals. Consequently, results may not be generalizable to transplant contexts in other countries.

Conclusion:

This study highlights the complexities of integrating molecular matching into organ allocation, raising concerns about equity, feasibility, and implementation. While HLA experts agree on the importance of ensuring equity and timely access, their perspectives also underscore the challenges of implementation, such as the availability of timely high-resolution HLA typing, stakeholder buy-in, and the need for dedicated tools and applications. To ensure an ethical and equitable implementation, future efforts must address access disparities through targeted mitigation strategies, such as the introduction of a maximum waiting time for a molecular-matched kidney.

Keywords

molecular matching kidney allocation qualitative study kidney transplantation HLA professionals

Introduction

Kidney transplantation is the preferred treatment for patients living with end-stage kidney failure, offering better survival odds and quality of life compared to dialysis.^1-3 However, graft loss remains a significant challenge in kidney transplantation, particularly in deceased donor transplants, where the 10-year graft survival rate is 54% in Canada.⁴ While multiple factors contribute to graft failure, rejection remains the leading cause, with antibody-mediated rejection (AMR) being the most severe and difficult to treat. The AMR can occur at any point in the transplant course, and its presentation ranges from the less common acute AMR, with rapid and fulminant graft injury, to the more common chronic AMR, with progressive graft injury.^5-9 The AMR is associated with the development of donor-specific antibodies, which occur when there is an immune recognition by the recipient of non-self HLA of the organ donor. As there are limited effective treatments for AMR, preventive strategies, including improved donor-recipient matching, are critical.

In Canada, provincial Organ Donation Organizations (ODOs) are responsible for organ recovery and allocation, as well as transplant coordination. The ODOs try to balance equity and utility when allocating organs, based on an array of factors such as time on dialysis, medical urgency, HLA compatibility, and pediatric priority.^10,11 Highly sensitized patients (ie, with a calculated panel reactive antibody or calculated panel reactive antibody [cPRA] >95%) may receive priority access to deceased donor kidneys through a national registry managed by Canadian Blood Services (CBS).¹²

To improve transplant outcomes, molecular-based matching has been proposed as a novel, more precise method for assessing HLA compatibility by analyzing amino acid variations that influence cellular and/or antibody responses (T-cell and B-cell epitopes, respectively).¹³ Molecular compatibility (previously referred to as epitope matching) could help reduce donor-specific antibody (DSA) formation and lower the risk of AMR.¹⁴ Responding to these recent advancements, the Genome Canada Transplant Consortium is developing a national molecular matching program in kidney transplantation aimed at reducing the incidence of rejection.¹⁵

Despite its potential benefits, integrating molecular matching into kidney allocation could raise ethical and logistical concerns.¹⁶ While it may improve long-term outcomes in some kidney recipients, it could also limit access to transplants for others, such as those with rare HLA profiles and racial minorities. Given a persistent organ shortage and the complexity of organ allocation, it is important to consider how and to what extent changes in current allocation policy might impact the Canadian population.

This study falls under the larger CanPREVENT AMR project, which seeks to use genetic technologies to improve donor-recipient matching and reduce the risk of AMR.¹⁵ One of the objectives of CanPREVENT AMR is to document the ethical issues associated with molecular-based matching in kidney allocation from various stakeholders’ perspectives. We have previously reported Canadian transplant professionals’ and patients’ perspectives on molecular matching in kidney transplantation.^17,18 These previous studies highlighted the need to further explore the perspectives of a specific subgroup of transplant professionals—HLA professionals—whose expertise in evaluating donor-recipient compatibility and minimizing the risk of graft rejection is essential to organ allocation and precision medicine. The objective of this study is to gather HLA professionals’ perspectives on the ethical and logistical issues related to molecular matching and precision medicine in kidney transplantation.

Methods

This study was exploratory in nature and used semi-structured interviews with HLA professionals. We used the consolidated criteria for the reporting qualitative research checklist.¹⁹ We conducted individual semi-structured interviews to gather HLA professionals’ perspectives on molecular compatibility in kidney transplantation. The Centre hospitalier de l’Université de Montréal research ethics board approved the study, and all participants provided informed consent (CE20.054, MP-02-2021-9021/F1H-105764, 2023-06-26).

Recruitment and interviews were carried out between January and June 2024. Convenience and purposive sampling²⁰ were used to recruit HLA professionals (immunologists working in HLA laboratories) across Canada. An invitation email was sent to 26 members of the National Human Leukocyte Antigen Advisory Committee (NHLAAC), a committee of the CBS, by the chair of the committee. In addition, one of the researchers (R.S.-P.) mentioned the study during a regular NHLAAC meeting. Three reminders were sent by email, and those interested were contacted by a research team member (F.B.) to schedule an interview date. The NHLAAC is characterized by a preponderance of male members and includes two to three representatives per province. Ten HLA professionals replied to the invitation and were interested in participating. Of those 10 experts, one had participated in a related prior study, one withdrew due to working exclusively with stem cells, and one could not be reached to schedule an interview date. Ultimately, seven HLA experts participated. Figure 1 summarizes the recruitment process.

Figure 1.

Flowchart for the recruitment process.

Seven participants took part in an individual interview. Of these, one was conducted by phone and six by videoconference; six in English and one in French. All interviews were facilitated by a male member of the research team who has more than 10 years of expertise in qualitative methods and no relationship with HLA professionals (F.B.). The interviews lasted around 44 (30-60) minutes and were digitally recorded and transcribed by a professional transcriptionist. All transcriptions were sent to participants for verification. One participant modified their transcription for clarification purposes, without changing the opinions expressed during the interview. These modifications were integrated into the final analysis.

Prior to the interviews, participants were briefed on the study objectives and given the opportunity to ask questions. The issues covered during the interviews were outlined in an interview guide comprising open-ended questions that was developed by the research team based on their previous work on the perspectives of kidney transplant professionals on molecular-based matching and kidney allocation.¹⁸ The interview guide previously designed for health care professionals was adapted to include more precise questions pertaining to the expertise of HLA professionals. Questions addressed the following topics: (1) perspectives on the current organ allocation system; (2) role of molecular-based matching in deceased and living organ donations; (3) implementation and challenges of precision medicine; and (4) recommendations for improving the allocation process. Participants were also asked to complete a separate online questionnaire designed to collect basic socio-demographic data (sex, age, race, type of job, province of practice, and years of experience). Consistent with qualitative methodology, the interview guide was modified during the study as new themes emerged from the interviews.²⁰ The finalized interview guide can be found in the Supplemental Material.

A qualitative description approach was employed to summarize the perspectives of HLA professionals on organ allocation and molecular matching.^21,22 The goal of this pragmatic approach was to stay close to the data and provide a comprehensive summary of the topic studied,²¹ using thematic analysis.²⁰ The latest version of NVivo 15.0.1 (Lumivero) software was used to facilitate coding and analysis. Prior to coding verbatim transcripts, the research team created an initial coding frame based on the interview guide and a review of the literature. New codes were added to the initial coding frame as new themes emerged from interview content. The research team met frequently to discuss the coding frame and data analysis.

A female research team member trained in qualitative methodology (L.A.) coded all interviews, and frequent team discussion ensured consistency in the coding process. A female independent researcher with more than 10 years of experience in qualitative methods (A.A.) coded 75% of the raw data. Discrepancies were resolved through discussion. The coded data were organized into themes and subthemes to provide a comprehensive summary of findings.

Results

Participants’ Characteristics

Of the seven participants, six were male and aged between 41 and 61. They worked in five Canadian provinces. All except one were HLA lab directors. Two described themselves as white, three as Asian or South Asian, and two as other categories. Table 1 summarizes participants’ characteristics.

Table 1.

Participants’ Characteristics.

Characteristics	HLA experts (n = 7)
Sex
Female/male	1/6
Age (years ± SD)	50.6 ± 6.3
(Range 41-61)
Race
White	2
Asian/South Asian	3
Other	2
Type of job
HLA lab director	6
HLA lab professional	1
Province of practice
Alberta	1
British Columbia	1
Ontario	2
Quebec	2
Saskatchewan	1
Years of experience in nephrology (±SD)	17 (7.3)
<10 years	1
10-19	4
20-30	1
>30	1

Perspectives on the Current Organ Allocation System and Allocation Criteria

Participants expressed generally positive feelings about the current allocation system but noted that improvements are needed, notably in terms of HLA matching (Box 1). Participants believed that HLA compatibility, maximizing graft survival, waiting time, medical urgency, age, race, and ABO blood group should be taken into account in a fair allocation algorithm. They used the term “race” to refer to the probability of having common ancestry, which they thought was an important consideration in organ allocation given that the frequency of HLA profiles varies across ancestry groups, which may make it difficult to find compatible organs for transplant candidates with other than European origins. In addition, experts suggest adjusting the allocation system to account for differences in access based on ABO blood group, as individuals with rare blood types may face more limited donor organ availability. In their opinion, adherence, having dependents, lifestyle habits, and needing a second transplant should not be considered as criteria.

Box 1.

Perspectives on the Current Organ Allocation System.

Themes and interview excerpts
The current allocation system is fair, but there is room for improvement “Yes, it’s an algorithm that’s been in place for several years now and needs to be optimised [. . .] there is perhaps a certain level of inequity, where we should perhaps have more of a gradual scale [. . .] it’s a system that works, but that needs notable improvements.” (HLA expert 1) “there is definitely room for improvement [. . .] We use CPRA to define a patient’s level of sensitization, but we know that is probably not the most accurate method to represent a particular individual patient’s true access to offers.” (HLA Expert 2) “They [the organ allocation systems] are not optimal [. . .] Because primarily, primarily, yes, the donors are donating to recipients who do not present HLA antibody, basically that’s it. They do not look at the level of matching between recipients and the donors.” (HLA expert 4) “I think that certainly there is room for improvement. One of the areas, like one of your research project is considering HLA matching.” (HLA expert 5)
Allocation criteria that needs to be considered in a fair allocation scheme 1. HLA Compatibility “I think it is very important because even with all this immunosuppressive that is being developed, still there is strong research suggesting that zero mismatchers do better than one antigen mismatch and two antigens mismatches and so on. So, I think actually HLA compatibility is still an important item.” (HLA expert 3) “We also need to have a better definition of compatibility, so not just considering HLA-DR compatibility that gives us a certain number of points, while the rest doesn’t count at all. (. . .) Being in an HLA laboratory, it’s obvious that this is the area I would emphasize on.” (HLA expert 1) “I think it should be considered in the allocation, particularly for pediatric patients. Cause quite often these patients most likely are going to need a second transplant or a third transplant down the road and those have a relatively long like long road ahead of them, so it is better to give them like a better match, a kidney so that there will be fewer antibodies generated after that [. . .] so they won’t become highly sensitized after the first kidney transplant.” (HLA expert 5) 1. Maximizing graft survival “The goal of the project is precisely to minimize the risk of rejection after the transplant as much as possible, so that is of crucial importance, because we want to perform a procedure that will last over time.” (HLA expert 1) “how much of those resources do you have. I give you an unlimited number of organs that all are going to last 20 years, sure, just put them into everybody. But you have only like two organs a year, you’ve got to make sure that you get 40 years worth out of those two organs.” (HLA expert 2) 1. Waiting time “Well, of course, because the longer you spend on dialysis, the higher the morbidity and risk of mortality, so we need to minimize the waiting time on the list as much as possible.” (HLA expert 1) “it is heavily weighted in our algorithm your wait time or your dialysis time, and I think that is a fair measure to use to prioritize patients. From a societal perspective, it is expensive to have these patients on dialysis for, you know, many, many years. From a patient perspective, it is like it is hard to manage their life.” (HLA expert 2) “the patients that are on the dialysis the longest time, I feel they should be receiving that organ if the organ is compatible with them HLA-wise, ok? And I think that is fair cause that is because they have been waiting long enough, right?” (HLA expert 5) “I know how tough dialysis is, so I think that, you know, if you get a kidney that may not last as long as someone else’s but you have waited your time, I think that that person should get it regardless of how long it is going to last.”(HLA expert 6) 1. Medical urgency “There are very clear guidelines on what constitutes medical urgency and that is fair, and I don’t think anyone would argue with that.”(HLA expert 2) “I agree the current policy is a medical emergency, that patient should be given the number one priority. That is absolutely the case, the medical urgency where the patient could die if they don’t receive that lifesaving organ for, at least for the case of kidney.” (HLA expert 5) 5. Age “I think that is fair because those children’s cases have multiple decades ahead of them and so, you know, you want to give them the best chance of succeeding for 50, 60, 70 years. So, you have to really give them the best options. If you start off with like mediocre options, trying to get them to 50, 60, 70 years down the line is going to be much harder, so it’s an upfront cost.”(HLA expert 2) “I hope to see a gradual scoring system that you give a lot of high priority to very young person, so that if they find a very well-matched donor, it is going to be working for them. The gradual scoring has to be that it increases scores slowly as they age.” (HLA expert 4) “We prioritize matching for pediatric, because we want to have them retain the organ longer.” (HLA expert 7)
6. Race “Some patients, depending on their ethnic background, may have HLAs that are a little rarer or a little less rare. So I think this should be taken into consideration to ensure equal equity for everyone.” (HLA expert 1) “If we give too many points to the HLA match, then it will disadvantage those waiting longer and the minority ethnic groups or, you know, the native Canadians with mixed ethnic backgrounds people, they will never be able to find any kind of match donor kidney out there. There will be a little bit of unfairness.” (HLA expert 5) 7. Consideration for blood group “Another aspect currently being looked at by CBS is evaluating patient access based on blood group. [. . .] A group O patient who only has access to group O donors should have a CPRA calculation that reflects the proportion of donors they can access. [. . .] They don’t have access to all donors, so there’s an inequity on that front as well.” (HLA expert 1) “I think it’s how many offers that this person will likely be provided is the main thing and that can be classified due to you know their sensitization, their, their ABO blood group is one of the rare ones, if, yes, so there are a couple of different metrics that might impact that, but it is their access to offers, yes.” (HLA expert 2)
Allocation criteria that should not be considered in a fair allocation scheme 1. Adherence “that is a moral issue as opposed to an ethical issue. I would say that it would be difficult for me to give someone a re-transplant if I knew that they were not adherent, and I knew going in that they would be non adherent. (. . .) I have been in situations where we see, there are several patients that are standing outside the hospital waiting for lung transplant smoking cigarettes and I’m like why am I giving you an organ? Because someone else is at home waiting, being very careful, looking after themselves, patiently waiting for their organ, and you might get it while you are smoking a cigarette which is because whatever, the allocation is for them, right? We’re talking about non-adherence to medication, but that is non-adherence to selfcare, right? Management of your physical body. They are all offered the organs of course, but it is disappointing when you know that you are taking it away from somebody else who wouldn’t do the same thing.” (HLA expert 2) “I don’t think I can judge a teenager because they will not adhere to therapy as less points or something. I could give extra points to someone who adhere, but I do not deduct point from someone who didn’t because that’s normal.”(HLA expert 3) 1. Having dependents “if you ask someone from the street, they might feel sympathy, but again the health of the patient and the safety is more important, so I don’t think we can put these patients at a higher priority than patients who actually need a kidney.”(HLA expert 3) 2. Lifestyle habits “it should not be included on the allocation, but it has to be looked at. [. . .] social worker and the nurses could use the opportunity to make sure the patients understand that, make them feel important that you know this is a new life, it is a new opportunity for them.” (HLA expert 4) 3. Retransplantation “No, I think regardless of whether it’s a first or a subsequent transplant, we should give equal priority. But again, a subsequent transplant is riskier because there’s prior immunization, which can lead to a higher risk of rejection. That said, I wouldn’t prioritize one over the other.” (HLA expert 1)
Medical utility vs fairness in kidney allocation Favoring fairness “I think me as an individual, I still think that, that you know, if, you know, if someone gets a kidney, you know, who am I to say that for someone three years is not great, right? Like let’s say you give someone a kidney and they have three years, and they get to see their grandkids more and they be around to know their grandkids, and it doesn’t last that long, and they die. Versus someone who gets a better match, and you know, and you know, and they get a longer kidney, but it is not for us to say what is more important, someone gets some time or someone gets more time. [. . .] even though kind of the scientist says maximize the utility, I think the human in me says that, you know, that could prevent individuals from getting a transplant and it shouldn’t.” (HLA expert 6) Favoring graft survival “I’d say both (laughs), but if we have to choose, I think what’s important is simply having grafts that are of better quality—well, by better quality, I mean giving the organ that will function the longest and most effectively for the patient.” (HLA expert 1) “maximize the graft survival would be the best choice here, because this is something that you can control. You cannot control [. . .] the access [to transplantation], so I think the maximize the transplants survival is my own opinion because the worst people who, to find them a suitable donor is the people who lose their transplant again and then they increase their comorbidity as well.” (HLA expert 3)

When asked whether organ allocation should prioritize medical utility or fairness, participants expressed varying opinions. For one participant, maximizing graft survival should be prioritized since it could be influenced by medical management and post-transplant care, whereas access to transplant is unpredictable and more difficult to control. By contrast, another participant mentioned that the duration of graft survival should not be the sole measure of transplant success.

Advantages and Challenges of Precision Medicine in Kidney Allocation

Participants had mixed opinions on the potential role of precision medicine in the current organ transplant allocation system (Box 2). They acknowledged that it could improve graft survival and help monitor immunosuppression based on molecular matching. However, they also highlighted uncertainties arising from the current state of knowledge. For instance, one participant stated that the role of molecular mismatch in graft rejection is unproven. Another participant mentioned the need to develop standardized cut-offs in molecular matching to guide clinical care. Finally, a participant mentioned that there are probably plenty of epitopes that have not yet been discovered. Participants were also concerned about decreasing access to transplant for all patients, as they might have to wait longer for a better match. This delay may be exacerbated for patients from certain marginalized groups, such as those who are homozygous for certain HLA alleles or belong to underrepresented ethnic communities.

Box 2.

Advantages and Challenges of Precision Medicine in Kidney Allocation.

Themes and interview excerpts
Advantages of precision medicine “So, everything goes hand in hand—better graft survival, better patient survival, improved quality of life for the patient, and fewer medical interventions needed. So, everything is positive on that front. [. . .] There’s also a lower risk of developing anti-HLA antibodies after the transplant.”(HLA expert 1) “molecular mismatch in adjusting immunosuppressives, I would be very strong advocate for that. I would say yes, we can adjust the dose of tacrolimus based on the number of mismatches, because theoretically if you have high number of mismatches, there is a high chance that you will develop a higher number of antibodies, so you might require to increase your dose of tacrolimus or of your immunosuppressives. So, I can use this part of, like I’m not against the molecular mismatch, I’m against the way people are using it.” (HLA expert 3)
Challenges of precision medicine 1. Uncertainties “I think it is interesting, probably biologically relevant. I think there is still a lot of unknown, but you know lots of things have happened that there were lots of unknown.” (HLA expert 2) “so most of this molecular mismatches are theories. They have not proven to be actually involved or as a role in rejection, it is all theoretic, it is all based on something we have seen and we have created some statistics. Most of the studies are done in a small number of patients. I have never seen a big study that has been done.” (HLA expert 3) “how do you set up your cut-off? Because, if I’m going to do the study in Saskatchewan, my cut-off may be different than the cut-off in Toronto, so we need to have a bigger study done across Canada and then we have to set up the cut-off, and then, and when we are going to set-up the cut-off, how, the difference between the cut-off, is it like one mismatch? Like we can say 10 mismatches is better than 11 and according which loci we are talking about. Are we combining the loci or we are talking about eight specific locus. And I think this is all the questions that we need an answer on it.”(HLA expert 3) “I do think there are some epitopes that haven’t been discovered [. . .]I think it would be challenging, you know? All the times when I am trying to identify an epitope, maybe I can, just like an epitope that covers 95% of them, of the antigens, but not all of them. So, there are some, you know, black boxes that can’t be filled, so what would you do with that antigen then?”(HLA expert 6) 2. Decreasing access to transplantation for patients “I think it’s a valid concern—to ensure that we don’t end up with a loss of equity, an increase in wait times, or reduced access to transplantation for certain individuals.” (HLA expert 1) “Another point is perhaps for patients who are homozygous [. . .] where, essentially, the number of epitopes that can be matched may be more limited. So, there might be fewer available donors for these individuals. This still needs to be modeled, but I’d say that’s a concern from that perspective.” (HLA expert 1) “there are some downsides. It may disadvantage some people. I don’t know who those people would be. I’m not sure it is as simple as you know right now the allocation disadvantages, ethnic minorities, I’m actually not sure that that is the case if we use a different method of eplets for example.” (HLA expert 2) “patients who have rare typing, who are non-white, non-white patients, they will have for sure longer waiting period because of the mismatches will be higher and then they will stay longer on the waiting list.” (HLA expert 3) “I hope I am wrong, but I do think there would be some race-based bias if we were to go full eplets, epitope based, you know, allocation.” (HLA expert 6) “it doesn’t work for all ethnicities, I mean minorities tend to not work well, as well when it comes to eplets analysis. So, in general, these tools are not tested well with minorities and so, we should be mindful of that as we design what are the future studies we are doing.” (HLA expert 7) 3. Logistical challenges “The main challenge will be implementing it at the IT level, I’d say, because as we know, these things always take forever—especially with the ongoing developments in HLA.” (HLA expert 1) “Yes, the sequence in nanopore still needs the hands-on time, a longer time to process it and the cost currently is significantly higher than real type. Real type is not that cheap, but it is still much cheaper than the nanopore sequencing. Nanopore each flow cross is very costly, sure you can reuse it, but reusing it might decrease the quality.” (HLA expert 5) “I think the labs would have a lot of work to do to become standardized and you know, moving as one.” (HLA expert 6) “the tools also should be readily, easily available for all our frontline, because currently we are a very limited number of individuals who actually are conducting this eplet analysis, between the medical director and maybe the fellows in training. And the reluctance is that these tools are not integrated with our current tools. They are starting now to integrate them, but they are not there yet.”(HLA expert 7) “if you are even using the rapid method of HLA typing for sequence, six hours for on call, for someone to ask the technologist to come in the middle of the night and do it, it is going to be very challenging”(HLA expert 3) “It is feasible, but there might be some pushback from our technologists, that means they have to stay here in the boat longer than their current platform. Usually they will, the thing is that they tend to stay shorter and shorter. They like the other rather than oh, you have to stay longer and longer for each call, then that might be a little bit pushback from that perspective.” (HLA expert 5) “you have to balance like to see, ok, the amount of money that it’s going to cost us to implement this, does it, is it actually worth to use this allocation of money onto this technique or save this money on something else? [. . .] double the staff means that instead of my budget, it’s like half a million, I would ask for a million and is that, is our province able to fund this one?[. . .] in order to be done, then every center in Canada needs to have these resources and again, you need to increase the staffing to do it.” (HLA expert 3)

Themes and interview excerpts

Advantages of precision medicine
“So, everything goes hand in hand—better graft survival, better patient survival, improved quality of life for the patient, and fewer medical interventions needed. So, everything is positive on that front. [. . .] There’s also a lower risk of developing anti-HLA antibodies after the transplant.”(HLA expert 1)
“molecular mismatch in adjusting immunosuppressives, I would be very strong advocate for that. I would say yes, we can adjust the dose of tacrolimus based on the number of mismatches, because theoretically if you have high number of mismatches, there is a high chance that you will develop a higher number of antibodies, so you might require to increase your dose of tacrolimus or of your immunosuppressives. So, I can use this part of, like I’m not against the molecular mismatch, I’m against the way people are using it.” (HLA expert 3)

Challenges of precision medicine
1. Uncertainties
“I think it is interesting, probably biologically relevant. I think there is still a lot of unknown, but you know lots of things have happened that there were lots of unknown.” (HLA expert 2)
“so most of this molecular mismatches are theories. They have not proven to be actually involved or as a role in rejection, it is all theoretic, it is all based on something we have seen and we have created some statistics. Most of the studies are done in a small number of patients. I have never seen a big study that has been done.” (HLA expert 3)
“how do you set up your cut-off? Because, if I’m going to do the study in Saskatchewan, my cut-off may be different than the cut-off in Toronto, so we need to have a bigger study done across Canada and then we have to set up the cut-off, and then, and when we are going to set-up the cut-off, how, the difference between the cut-off, is it like one mismatch? Like we can say 10 mismatches is better than 11 and according which loci we are talking about. Are we combining the loci or we are talking about eight specific locus. And I think this is all the questions that we need an answer on it.”(HLA expert 3)
“I do think there are some epitopes that haven’t been discovered [. . .]I think it would be challenging, you know? All the times when I am trying to identify an epitope, maybe I can, just like an epitope that covers 95% of them, of the antigens, but not all of them. So, there are some, you know, black boxes that can’t be filled, so what would you do with that antigen then?”(HLA expert 6)
2. Decreasing access to transplantation for patients
“I think it’s a valid concern—to ensure that we don’t end up with a loss of equity, an increase in wait times, or reduced access to transplantation for certain individuals.” (HLA expert 1)
“Another point is perhaps for patients who are homozygous [. . .] where, essentially, the number of epitopes that can be matched may be more limited. So, there might be fewer available donors for these individuals. This still needs to be modeled, but I’d say that’s a concern from that perspective.” (HLA expert 1)
“there are some downsides. It may disadvantage some people. I don’t know who those people would be. I’m not sure it is as simple as you know right now the allocation disadvantages, ethnic minorities, I’m actually not sure that that is the case if we use a different method of eplets for example.” (HLA expert 2)
“patients who have rare typing, who are non-white, non-white patients, they will have for sure longer waiting period because of the mismatches will be higher and then they will stay longer on the waiting list.” (HLA expert 3)
“I hope I am wrong, but I do think there would be some race-based bias if we were to go full eplets, epitope based, you know, allocation.” (HLA expert 6)
“it doesn’t work for all ethnicities, I mean minorities tend to not work well, as well when it comes to eplets analysis. So, in general, these tools are not tested well with minorities and so, we should be mindful of that as we design what are the future studies we are doing.” (HLA expert 7)
3. Logistical challenges
“The main challenge will be implementing it at the IT level, I’d say, because as we know, these things always take forever—especially with the ongoing developments in HLA.” (HLA expert 1)
“Yes, the sequence in nanopore still needs the hands-on time, a longer time to process it and the cost currently is significantly higher than real type. Real type is not that cheap, but it is still much cheaper than the nanopore sequencing. Nanopore each flow cross is very costly, sure you can reuse it, but reusing it might decrease the quality.” (HLA expert 5)
“I think the labs would have a lot of work to do to become standardized and you know, moving as one.” (HLA expert 6)
“the tools also should be readily, easily available for all our frontline, because currently we are a very limited number of individuals who actually are conducting this eplet analysis, between the medical director and maybe the fellows in training. And the reluctance is that these tools are not integrated with our current tools. They are starting now to integrate them, but they are not there yet.”(HLA expert 7)
“if you are even using the rapid method of HLA typing for sequence, six hours for on call, for someone to ask the technologist to come in the middle of the night and do it, it is going to be very challenging”(HLA expert 3)
“It is feasible, but there might be some pushback from our technologists, that means they have to stay here in the boat longer than their current platform. Usually they will, the thing is that they tend to stay shorter and shorter. They like the other rather than oh, you have to stay longer and longer for each call, then that might be a little bit pushback from that perspective.” (HLA expert 5)
“you have to balance like to see, ok, the amount of money that it’s going to cost us to implement this, does it, is it actually worth to use this allocation of money onto this technique or save this money on something else? [. . .] double the staff means that instead of my budget, it’s like half a million, I would ask for a million and is that, is our province able to fund this one?[. . .] in order to be done, then every center in Canada needs to have these resources and again, you need to increase the staffing to do it.” (HLA expert 3)

Participants also mentioned logistical challenges associated with precision medicine and molecular matching. Moving forward with molecular matching will entail more working hours for HLA staff, acquiring technology that allows for high-resolution typing and additional funding to implement this new technology.

Role of Precision Medicine in Living Kidney Transplantation

Participants had a positive perspective on the use of precision medicine in kidney-paired donation (KPD) (Box 3). They saw value in incorporating molecular matching into the existing algorithm to help optimize donor-recipient compatibility, as long as this does not disadvantage certain patients. Since KPD operates on a national scale with predefined matching criteria, some participants suggested that molecular-based matching be integrated into the existing scoring system in a similar way to how HLA matching is currently used.

Box 3.

Role of Precision Medicine in Living Kidney Transplantation.

Themes and interview excerpts
“You are going into a national living pool, and you are already, there is already an algorithm that takes in account the optimal match based on these criteria which we know. You could include, because you have a national pool anyways, include epitope information into that list and like no, as long as it doesn’t disadvantage [. . .] anyone. You just keep on running the algorithm until you get your matches in the same way that it is currently done and there are scores, points allocated for [. . .] antigen match.” (HLA expert 2) “Yes, for, for kidney paired donors, I think it is much feasible to use it, but it shouldn’t, it shouldn’t be as, not as a priority I’m thinking, but could be as an optional tool that you can prioritize one over the other, but it should not be in the priority list, but it could be some sort of an optional, like same as age.”(HLA expert 3) “Yes, this idea sounds good, but the reality isn’t as, as far as I know, many directed donations, they just want to donate to that, to their loved ones, friends and direct donation [. . .] Unless they are not compatible, they don’t have any choice, but when they are compatible, a lot of them want to, hey, this is much simpler [. . .] Very few people actually would jump to that kind of altruistic, a little bit altruistic, donation.” (HLA expert 5) “I think a living donor mismatched kidney will trump a deceased donor match kidney. [. . .] Of course, a living donor perfectly matched will be better than just unrelated living donor, but if a living donor [mis]matches versus a deceased donor match, I think many programs will go with the living donor, yes.” (HLA expert 5) “Now, to expand that to having a better eplet matching. Again, that is going to come with the willingness of the patient to wait or not [. . .] you have to balance between that harm and now long that patient would have to wait.” (HLA expert 7)

Themes and interview excerpts

“You are going into a national living pool, and you are already, there is already an algorithm that takes in account the optimal match based on these criteria which we know. You could include, because you have a national pool anyways, include epitope information into that list and like no, as long as it doesn’t disadvantage [. . .] anyone. You just keep on running the algorithm until you get your matches in the same way that it is currently done and there are scores, points allocated for [. . .] antigen match.” (HLA expert 2)
“Yes, for, for kidney paired donors, I think it is much feasible to use it, but it shouldn’t, it shouldn’t be as, not as a priority I’m thinking, but could be as an optional tool that you can prioritize one over the other, but it should not be in the priority list, but it could be some sort of an optional, like same as age.”(HLA expert 3)
“Yes, this idea sounds good, but the reality isn’t as, as far as I know, many directed donations, they just want to donate to that, to their loved ones, friends and direct donation [. . .] Unless they are not compatible, they don’t have any choice, but when they are compatible, a lot of them want to, hey, this is much simpler [. . .] Very few people actually would jump to that kind of altruistic, a little bit altruistic, donation.” (HLA expert 5)
“I think a living donor mismatched kidney will trump a deceased donor match kidney. [. . .] Of course, a living donor perfectly matched will be better than just unrelated living donor, but if a living donor [mis]matches versus a deceased donor match, I think many programs will go with the living donor, yes.” (HLA expert 5)
“Now, to expand that to having a better eplet matching. Again, that is going to come with the willingness of the patient to wait or not [. . .] you have to balance between that harm and now long that patient would have to wait.” (HLA expert 7)

That being said, participants acknowledged that living donor transplants offer superior outcomes compared to deceased donor transplants, raising the question of how much additional benefit molecular-based matching would provide in this situation. They mention that, in practice, an available but mismatched living donor would often offer a better outcome than waiting for a better-matched deceased donor. Decisions also depend on how long a patient is willing or able to wait for an optimal match.

In addition, participants noted that those entering the KPD program often do so because their initial intended donor was incompatible, and they join the pool in the hope of finding a better match. Some suggest that molecular-based matching should be used as an optimizing tool but emphasize the need to remain flexible in its application.

Recommendations for the Implementation of Precision Medicine in Kidney Allocation

One of the recommendations made by HLA professionals was to set a maximum waiting time for a molecularly matched kidney (Box 4). They did not specify how long this maximum waiting time should be, but they said that it should be adapted to each patient’s situation and should not exceed the average waiting time. If a patient waits longer than the maximum wait time that has been set, they should have access to the regular organ donation pool.

Box 4.

Recommendations for the Implementation of Precision Medicine in Kidney Allocation.

Themes and interview excerpts
1. Setting a maximal waiting time “we would weight your, like give you a weighted score, so that you would be bumped up the priority list, or we would say ok, you are, on the current algorithm, allocation algorithm, your predicted wait time is two years, so on the new algorithm if you don’t get an offer by two years, the 1st organ that comes on, you know, two years and one day is yours. It doesn’t matter, so you would not wait any longer than you would right now.” (HLA expert 2) “it shouldn’t be more than five-to-six-to-seven years, because otherwise, what is the benefit of it? So, at least, at least it should match what we have now, but not longer.” (HLA expert 3) 2. Conducting research and reassessing the program “We need to run tests on larger, more diverse populations to truly ensure that there will be zero ethical issues—because every population or every patient must have an equal chance of accessing a transplant.” (HLA expert 1) “[M]aybe we should reconsider things, and these systems aren’t meant to be implemented ad vitam aeternam, and I think that’s something we really need to encourage. [. . .] Whether it’s at the level of Canadian Blood Services or [local organism], we need to question ourselves and reassess—ask whether something needs to be changed.”(HLA expert 1) “We are actively using what is available, but it is more research on, research based on case by case, so we are not able now to use this on all patients, and the few patients that are difficult, we tend to spend a lot of time working up with different tools, but I think that we are going on the right direction.” (HLA expert 7) 3. Mitigation strategies “[If] our modeling shows that this type of genetic makeup makes them, gives them less access to offers, so we will probably list them on the national list or, you know, homozygosity gets twice as many score as someone who is not homozygous an attempt to bring down their wait time.” (HLA expert 2) “Well, the only thing is that you need to give them extra points, like put them at a higher priority or something like this. They have to get more extra points.” (HLA expert 3) 4. Standardization of HLA laboratories “Having a new technique is not too difficult and then they also like try to standardize the way that technique is implemented to a greater or a lesser extent.” (HLA expert 2) “I think the labs would have a lot of work to do to become standardized and you know, moving as one. [. . .] there would have to be some really big standardization, you know, within Canada, within the HLA community to make sure everyone is calling the right epitope.” (HLA expert 6)
5. Nationwide collaboration and allocation “national allocation would help kind of spread it out because, you know, certain ethnic areas would, you know, like if someone is, you know, an African trying to get an organ in Winnipeg, he might not have an easy time as an African having to get an organ in Toronto or in Quebec [. . .] maybe there needs to be more of a national based allocation.”(HLA expert 6) “It should be national because we all share organs. Like I get organs from Vancouver, I get organs from Edmonton, I can send organs to Halifax.” (HLA expert 3) “Yes, I think it is possible, but until every province have their system ready we all can upgrade to the national allocation process. If certain provinces are not ready, they will actually chose to implement it later, yes, it might be fine to.” (HLA expert 4) “small province would lose because we will find that we are giving all our organs to nationally. The ones that would gain are the bigger provinces.” (HLA expert 3) “if we have a national allocation, that will create another barrier in there because Canada is such a large country, right? So, if you allocate HLA match kidney from a BC to Halifax, the added code-ischemic time probably negate all the benefits of HLA matching.” (HLA expert 5) 6. Education and engagement of health care professionals “Engage a clinical teams as soon as possible, like yesterday. [. . .] Because one, we HLA labs talk about eplets, have been talking about eplets for years and we have been training our physicians, so that at least mentally they are aware that there is this thing happening. Some physicians may not even know what an eplet is, so you need to educate them before they can even change, have the discussion about how to change the algorithm. So, engage clinicians, local clinicians, nephrologists like yesterday (Laughs).”(HLA expert 2)

Themes and interview excerpts

1. Setting a maximal waiting time
“we would weight your, like give you a weighted score, so that you would be bumped up the priority list, or we would say ok, you are, on the current algorithm, allocation algorithm, your predicted wait time is two years, so on the new algorithm if you don’t get an offer by two years, the 1st organ that comes on, you know, two years and one day is yours. It doesn’t matter, so you would not wait any longer than you would right now.” (HLA expert 2)
“it shouldn’t be more than five-to-six-to-seven years, because otherwise, what is the benefit of it? So, at least, at least it should match what we have now, but not longer.” (HLA expert 3)
2. Conducting research and reassessing the program
“We need to run tests on larger, more diverse populations to truly ensure that there will be zero ethical issues—because every population or every patient must have an equal chance of accessing a transplant.” (HLA expert 1)
“[M]aybe we should reconsider things, and these systems aren’t meant to be implemented ad vitam aeternam, and I think that’s something we really need to encourage. [. . .] Whether it’s at the level of Canadian Blood Services or [local organism], we need to question ourselves and reassess—ask whether something needs to be changed.”(HLA expert 1)
“We are actively using what is available, but it is more research on, research based on case by case, so we are not able now to use this on all patients, and the few patients that are difficult, we tend to spend a lot of time working up with different tools, but I think that we are going on the right direction.” (HLA expert 7)
3. Mitigation strategies
“[If] our modeling shows that this type of genetic makeup makes them, gives them less access to offers, so we will probably list them on the national list or, you know, homozygosity gets twice as many score as someone who is not homozygous an attempt to bring down their wait time.” (HLA expert 2)
“Well, the only thing is that you need to give them extra points, like put them at a higher priority or something like this. They have to get more extra points.” (HLA expert 3)
4. Standardization of HLA laboratories
“Having a new technique is not too difficult and then they also like try to standardize the way that technique is implemented to a greater or a lesser extent.” (HLA expert 2)
“I think the labs would have a lot of work to do to become standardized and you know, moving as one. [. . .] there would have to be some really big standardization, you know, within Canada, within the HLA community to make sure everyone is calling the right epitope.” (HLA expert 6)

5. Nationwide collaboration and allocation
“national allocation would help kind of spread it out because, you know, certain ethnic areas would, you know, like if someone is, you know, an African trying to get an organ in Winnipeg, he might not have an easy time as an African having to get an organ in Toronto or in Quebec [. . .] maybe there needs to be more of a national based allocation.”(HLA expert 6)
“It should be national because we all share organs. Like I get organs from Vancouver, I get organs from Edmonton, I can send organs to Halifax.” (HLA expert 3)
“Yes, I think it is possible, but until every province have their system ready we all can upgrade to the national allocation process. If certain provinces are not ready, they will actually chose to implement it later, yes, it might be fine to.” (HLA expert 4)
“small province would lose because we will find that we are giving all our organs to nationally. The ones that would gain are the bigger provinces.” (HLA expert 3)
“if we have a national allocation, that will create another barrier in there because Canada is such a large country, right? So, if you allocate HLA match kidney from a BC to Halifax, the added code-ischemic time probably negate all the benefits of HLA matching.” (HLA expert 5)
6. Education and engagement of health care professionals
“Engage a clinical teams as soon as possible, like yesterday. [. . .] Because one, we HLA labs talk about eplets, have been talking about eplets for years and we have been training our physicians, so that at least mentally they are aware that there is this thing happening. Some physicians may not even know what an eplet is, so you need to educate them before they can even change, have the discussion about how to change the algorithm. So, engage clinicians, local clinicians, nephrologists like yesterday (Laughs).”(HLA expert 2)

For HLA professionals who participated in this study, it appears of paramount importance to revisit the policy or program regularly and to conduct research. One participant mentioned that future policy should be reassessed to ensure that there are no unintended consequences or disadvantage to any group of patients. In addition, mitigation strategies could be implemented through a modified point system for patients from such populations. Implementing molecular matching will also require nationwide collaboration and allocation, standardization amongst HLA laboratories, and education of physicians and patients. There is also a need for further research on molecular-based matching, epitope matching, and outcomes.

When asked whether we should shift from a provincial to a national kidney allocation system with the implementation of molecular-based matching, participants’ opinions were divided. Many viewed a national allocation system as a way to improve access to molecular-matched kidneys. By contrast, some participants raised potential logistical challenges arising from geographical distance in Canada and possible inequities for smaller provinces.

Discussion

This is the first study to report HLA professionals’ perspectives on precision medicine application to improve molecular compatibility in kidney transplantation. The HLA professionals identified benefits of integrating molecular matching for improving graft survival and reducing the incidence of kidney rejection. There are many similarities between HLA professionals’ perspectives and those of patients and transplant professionals that we have previously reported. Patients as well as transplant and HLA professionals all expressed concerns about the risk of decreasing access to donor kidneys for certain groups of patients, and they all suggested setting a minimal waiting time for a molecular-matched kidney.^17,18

Disadvantaging certain groups of patients is a common concern for patients and for transplant and HLA professionals. With current HLA matching, there are existing disparities whereby white transplant candidates have a higher chance of finding a zero mismatch HLA-A,B,DR donor than black or Asian recipients.²³ It is currently uncertain if this concern is founded in the case of molecular-based matching. Recently, Mangiola et al²⁴ showed that that there is a relatively uniform distribution of HLA eplets across diverse population groups. Another study has shown that giving priority to low HLA-DR and/or HLA-DQ eplet mismatch would not increase disparities in access to deceased donor transplantation for black and Latino transplant recipients.²³ Future prospective studies are needed to document whether molecular-based matching impacts access to transplantation for some ethnic groups.

In contrast to the participants of our previous studies, HLA professionals were particularly concerned about knowledge gaps around molecular-based matching. Their concerns concur with the knowledge gaps identified with the Sensitization in Transplantation: Assessment of Risk workgroup.²⁵ This working group is a collaborative effort between the American Society of Transplantation and the American Society for Histocompatibility and Immunogenetics. Its objective is to identify knowledge gaps, establish research priorities, and provide guidance in the field of histocompatibility matching and organ transplantation.²⁵ This could be explained by their awareness of recent developments in the field. Moreover, there is current evidence of a relationship between molecular incompatibilities, the development of de novo DSA, and graft loss. However, this evidence is based on retrospective studies, and there are no established clear cut-offs of molecular mismatch that would contraindicate kidney transplantation.^26-29

The HLA professionals highlighted the technical and logistical challenges associated with the implementation of molecular-based matching. Molecular-based matching requires high-resolution HLA genotyping, which is not universally available, is costly, and needs to be performed in a timely manner for deceased donor transplantation.³⁰ Currently, low- or intermediate-resolution molecular HLA genotyping is the standard method in deceased kidney transplantation because of the required speed of testing.³¹ In addition, implementing molecular-based matching will require increased resources in terms of funding and staffing in HLA laboratories. Future health economics studies are needed to assess the costs of molecular-based matching and the costs of graft loss and AMR for health care systems.

Participants expressed mixed views on the role of molecular matching in living donor transplantation, particularly within KPD programs. They acknowledged that molecular-based matching could theoretically improve the success of living donor kidney transplants by optimizing donor-recipient compatibility. However, they also noted that living donor transplants already offer superior outcomes compared to deceased donor transplants, raising the question of whether molecular-based matching would provide significant additional benefits in this setting, particularly if it delayed access to living donor transplantation. To improve molecular matching in KPD, it is critical to have a sufficient number of pairs registered. It could also involve recruiting compatible pairs to participate in KPD in order to improve their molecular match.^30,32 Recently, the National Kidney Registry in the United States integrated molecular-based matching as a tie breaker in the allocation of living donor kidneys through voucher donation.³³ Future studies are needed to document the positive impacts of molecular-based matching in living donor kidney transplantation.

The limitations of our study include its small sample size, which means that results may not reflect the perspectives of other HLA professionals. However, Canadian HLA professionals are a small community, and we were able to gather the views of seven of the 26 members of the National Human Leukocyte Antigen Advisory Committee. Also, most participants were male, which could be explained by the overrepresentation of men in the NHLAAC. In addition, they were highly educated on the technical aspects of molecular matching, which could have influenced their views on the ethical issues related to this topic.

Conclusion

This is the first study to report HLA professionals’ perspectives on molecular-based matching in kidney allocation. Their perspectives enrich our previous work with patients and transplant professionals. The HLA professionals shared some of the concerns expressed by patients and transplant professionals, such as the uncertainties related to this type of matching and the risk of disadvantaging some populations in accessing kidney transplant. However, given their expertise in the field of HLA, they additionally emphasized knowledge gaps and logistical challenges related to molecular-based matching. In the process of integrating molecular compatibility into kidney allocation in Canada, documenting HLA professionals’ perspectives will contribute to the development of an evidence-based and ethical framework for organ allocation.

Supplemental Material

sj-docx-1-cjk-10.1177_20543581251412195 – Supplemental material for HLA Experts’ Perspectives on Precision Medicine and Molecular Matching in Kidney Transplantation: A Qualitative Study

Supplemental material, sj-docx-1-cjk-10.1177_20543581251412195 for HLA Experts’ Perspectives on Precision Medicine and Molecular Matching in Kidney Transplantation: A Qualitative Study by Lucy An, Aliya Affdal, Fabian Ballesteros, Marie-Françoise Malo, Savannah-Lou Cochran-Mavrikakis, Carina Sancho, Noémi Tousignant, Stirling Bryan, Paul Keown, Ruth Sapir-Pichhadze and Marie-Chantal Fortin in Canadian Journal of Kidney Health and Disease

Footnotes

ORCID iDs

Lucy An

Ruth Sapir-Pichhadze

Marie-Chantal Fortin

Ethical Considerations

The Centre hospitalier de l’Université de Montréal research ethics board approved the study, and all participants provided informed consent (CE20.054, MP-02-2021-9021/F1H-105764, 2023-06-26). This research was conducted according to the World Medical Association Declaration of Helsinki.

Author Contributions

L.A. participated in the data analysis and in the writing of the manuscript.

A.A. participated in the conduct of the research and the data analysis and in the writing of the manuscript.

F.B. participated in the conduct of the research and the data analysis and in the writing of the manuscript.

M.-F.M. participated in the writing of the manuscript.

S.-L.C.-M. participated in the data analysis and in the writing of the manuscript.

C.S. participated in the data analysis and in the writing of the manuscript.

N.T. participated in the writing of the manuscript.

S.B. participated in the research design and in the writing of the manuscript.

P.K. obtained the research funding and participated in the research design and in the writing of the manuscript.

R.S.-P. obtained research funding and participated in the research design, conduct of research, and in the writing of the manuscript.

M.-C.F. participated in the research design, in the conduct of the research and the data analysis, and in the writing of the manuscript.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research project was funded by the Genome Canada Large Scale Applied Research Program Award “Precision Medicine CanPREVENT AMR,” funded by Génome Québec, Genome British Columbia, Genome Alberta, and the Canadian Institutes of Health Research. Drs R.S.-P. and M.-C.F. are Fonds de recherche du Québec—Santé research scholars. They are also Canadian Donation and Transplantation Research Program investigators. We want to thank all those who took the time to participate in this study.

Declaration of Conflicting Interests

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: F.B., A.A., M.I., M.-F.M., C.S., S.-L.C.-M., S.B., P.K., R.S.-P., and M.-C.F. have no conflicts of interest to declare.

Supplemental Material

Supplemental material for this article is available online.

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Supplementary Material

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