At a glance Current policy Calculated Panel Reactive Antibody (CPRA) is a formula used to determine what proportion of deceased donors a potential candidate may be immunologically incompatible with and unable to accept organs from; in other words, how “sensitized” a candidate is. The more highly sensitized a candidate is, the fewer donors from which they’d be able to accept offers. The current formula is not as specific as it could be, so the OPTN Histocompatability Committee proposes updating it to better evaluate how sensitized a patient is and make sure the patient receives the most appropriate priority for allocation. Supporting media Presentation View presentation Proposed changes Use of National Marrow Donor Program (NMDP) data for the new CPRA formula, which includes over a hundred times more data than the OPTN data set. Addition of three new loci to the formula, so that candidates who are sensitized at these will receive appropriate priority. Addition of allele-level, or more specific, antibody values in the new formula. This allows candidates who have allele-level antibodies to receive prioritization while still being able to receive compatible donor offers typed at serologic antigen equivalents, which are less specific. Expansion of the ethnic groups utilized in approximating the deceased donor population to more accurately and inclusively represent potential donors. Change from a kidney-based deceased donor population to a population inclusive of all organs, to better approximate the potential donors for all waiting list candidates. Anticipated impact What it's expected to do Increase highly sensitized candidates’ access to transplant. Women and African American candidates will be most affected. More efficiently and accurately measure a candidate’s sensitization Change some candidates’ allocation priority What it won't do Not expected to treat any candidates less favorably than the current calculation Not expected to treat any particular population less favorably than the current calculation Terms to know Calculated Panel Reactive Antibody (CPRA): An algorithm used to determine what proportion of deceased donors a potential candidate may be unable to accept due to immunologic incompatibility. Human leukocyte antigen (HLA): Proteins that differentiate between self and non-self. Allele: One of two or more versions of a gene, which in the context of organ transplant normally refers to the genes that create HLA proteins on the surface of a cell. Often this term is used to refer to a higher resolution typing of HLA typing, which is more specific than the serologic antigen-level HLA typing. Antigen: An antigen is the protein on the surface of a cell that can induce an immune response. In the context of organ transplant, an antigen normally refers to the HLA of a candidate or donor. Often this term is used to refer to “serologic antigens”, or the broader reactivity groups that the different alleles can fall into. Unacceptable Antigen: Alleles or antigens that a potential candidate has a high level of antibodies toward, and therefore would not be able to accept a donor with these HLA due to immunologic incompatibility. Loci: Locations on a chromosome where genes are found. There are 11 HLA loci primarily used in evaluation of organ compatibility. The current CPRA calculation includes 8 of these loci, and the proposed calculation includes all 11 loci. Sensitization: Transplant candidates are "sensitized" if their immune system makes antibodies against one or more HLA antigens or alleles in the donor pool. Sensitization usually occurs as a consequence of pregnancy, blood transfusions, or previous transplantation. Highly sensitized patients are less likely to match with available donors and more likely to reject an organ than unsensitized patients. Click here to search the OPTN glossary Comments UC San Diego Health Center for Transplantation | 03/23/2022 CASD is strongly in agreement with the revisions to the CPRA calculation as the proposed calculation is more predictive of potential organ compatibility, allowing histocompatibility labs to better assess a candidate’s likelihood of positive crossmatch. We believe that these modifications will benefit patients who appear to have a low cPRA but are difficult to match due to atypical antibodies and as a result promote access to transplantation and achieve best utilization of donated organs. It would absolutely be beneficial if all organ programs were able to view cPRA for all candidates and not just those that use cPRA for allocation; it would be helpful in waitlist management particularly for candidates who may be listed for multiple organs and managed by more than one transplant team (ex: heart and liver); and although it may not influence organ acceptance practices, having access to this information may be useful to some teams in determining whether or not there is a need for modification to immunosuppression regimens. The proposed transition plan of two months for entry of HLA-DPA1 unacceptable antigens and one week for HLA laboratory director and listing physician or surgeon approval for kidney candidates that would be over a cPRA of 99% may be difficult for some centers, particularly those with a larger volume of listed candidates, but it is not unreasonable. We acknowledge that historically disadvantaged candidates who stand to benefit from this change will not in fact benefit until after implementation so as long as the OPTN is able to provide resources or tools to assist programs with the transition, the proposed timeline is acceptable. David Maurer | 03/23/2022 I do not support the proposal as written for the following reasons: 1. The original KAS policy proposals included extensive modeling of the effect of using CPRA on deceased donor kidney offer rates. The current proposal to change CPRA lacks similar modeling which would be important to consider since CPRA is a kidney allocation calculator. 2. Hematopoietic stem cell transplant donors are typed at a higher resolution than are solid organ donors. Nevertheless, NMDP matching algorithms make frequent use of p-group matching wherein alleles without primary sequence differences in the antigen recognition domain (ARD) are counted as identical. Primary sequence differences that contribute to HLA antigenicity may reside outside the ARD: the HLA Epitope Registry lists 20 such ABC, 34 such DR, 13 such DQB, 8 such DQA, 4 such DPB and 7 such DPA structural epitopes. In calculating HLA frequencies, it would be important not to conflate alleles with ARD equivalency as having antigenic equivalency for this reason. The proposal takes pains to state that NMDP data collected at a higher level of resolution from 2015 on will be used to determine HLA allele frequencies. But much of the analysis in this proposal is based on NMDP typing data from as early as 2005 wherein no such distinction was drawn. (e.g. footnote 21). I would like to have seen all the analysis conducted on “clean” post-2015 data. Whether or not the proposal is adopted, consider that CPRA is now an entrenched part kidney transplant evaluation. At my transplant center, it is reported routinely in the patient’s EMR whenever pre- and post-transplant antibody tests are submitted. The web-based OPTN CPRA calculator is unsuitable for this purpose; instead, we use a CPRA calculator emulator that is part of the commercial HLA informatics software used in many histocompatibility labs, including mine. It will be important to make the calculation and frequency tables used by the proposed new CPRA calculator available in a time frame that will permit it to be incorporated by vendor softwares and to be vetted by transplant center information technology departments. The proposed transition time of one week is entirely inadequate. A phase-in that is too rapid may be highly disruptive. Pancreas Transplantation Committee | 03/23/2022 The Pancreas Committee thanks the OPTN Histocompatibility Committee for the opportunity to review their proposal. The Committee provides the following feedback: The Committee agreed with this proposal and thinks it’s great that other loci are being included in the calculation and there will be some additional priority. The Committee commented that one week seemed to be a quick turnaround time for the CPRA verification forms to be completed. The Committee also suggested that the OPTN Histocompatibility Committee review outcomes data of highly sensitized patients since (1) they are currently being highly prioritized and (2) it would be helpful to understand the effect of that prioritization on kidney allocation; specifically, are highly sensitized patients being transplanted regardless of how long the organ is expected to function in the patient? Members also highlighted that decisions are still being made about how high sensitization will be weighted in continuous distribution of kidneys and pancreata. Heart Transplantation Committee | 03/23/2022 The OPTN Heart Transplantation Committee (Committee) appreciates the opportunity to provide feedback on the OPTN Histocompatibility Committee’s Change Calculated Panel Reactive Antibody (CPRA) Calculation proposal. Committee members noted that having CPRA viewable for candidates may not currently have value in the heart transplantation community because of the variability in reporting, but also discussed that there are some programs that utilize this data so supported having the data viewable. The Committee added that the inclusion of CPRA independent of what is entered as unacceptable would also be helpful for programs so they could see the full picture. Committee members expressed some concern over candidates’ perceived impacts on availability of donors as part of patient counseling. Region 6 | 03/23/2022 3 strongly support, 7 support, 0 neutral/abstain, 0 oppose, 0 strongly oppose Humana | 03/23/2022 Humana supports the proposed change to the CPRA formula and the efforts to increase donor availability to candidates who otherwise may have had difficulty finding a histocompatible match. We are encouraged by the expected impact of this formula change to increase highly sensitized candidates’ access to transplant, particularly women and African Americans, as noted by the Histocompatibility Committee. American Society of Transplantation | 03/22/2022 The American Society of Transplantation is supportive of the proposal and offers the following comments: We support the inclusion of HLA-DPA1/DPB1/DQA1 and the use of a larger, more diverse, and fully HLA typed stem cell donor population in the new CPRA calculation. Waiting list candidates with sensitization toward these missing HLA loci have long been disadvantaged by the loss of the relevant allocation points. The extension of the CPRA calculation to 6 digits will provide better equity in allocating donors for the most highly sensitized patients. We support having CPRA viewable for all candidates. We anticipate that implementation of the new CPRA calculator will result in changes to the %CPRA for waiting list candidates. We recommend transplant programs be given a month to obtain the documentation for patients who will now be >98% CPRA due to these changes, rather than the one week proposed. Attachment MedStar Georgetown University Hospital | 03/22/2022 We would like to thank the Histocompatibility Committee for all their efforts and leadership on this proposal. We support the revision of CPRA calculation by incorporating HLA-DQA1, DPA1, and DPB1 antigens as well as allele-specific antibodies. We also support that CPRA should be viewable for all candidates. One question we have is how CPRA will be calculated in the presence of antibody against a shared DPB1 epitope (e.g. 84DEAV) if not all individual alleles are listed as UA? We propose extending the transition period to one month. Region 2 | 03/22/2022 7 strongly support, 15 support, 0 neutral/abstain, 0 oppose, 0 strongly oppose Steven Goldstein | 03/22/2022 Thank you for your efforts. Adding DQA1 and DPB1, and improving the calculator's handling of HLA linkage would be welcome changes. I strongly oppose the routine inclusion of allelic antibodies into the cPRA calculation. While allelic antibodies are fairly common, the number of patients who are severely disadvantaged by not including them in the calculation is very few. Listing alleles as unacceptable rather than the parent antigen will slow organ allocation by increasing the number of offers rejected on virtual or physical crossmatch. Additionally, the inclusion of allelic antibodies opens up the system to abuse. Because donors are currently typed at only antigen level resolution, adding allelic antibodies to UNet for a particular patient would increase cPRA and allocation points while excluding no organ offers. The proposed oversight to prevent abuse of this system is minimal. If the committee feels it is necessary to have this option for the rare patient significantly disadvantaged, I suggest developing a process in which a program must specifically apply to include allelic antibodies for a particular patient. There should be stringent criteria for approval, and robust review of accepted offers for these rare patients. Region 11 | 03/21/2022 Sentiment: 4 strongly support, 6 support, 3 neutral/abstain, 0 oppose, 0 strongly oppose. Comments: No additional comments. NATCO | 03/21/2022 NATCO appreciates the opportunity to comment on this proposal to Change the cPRA Calculation. Looking into the CPRA calculation is long overdue and we appreciate all the time and work that has gone into the committee’s proposal. We therefore support the effort to better evaluate how sensitized a patient is and make sure the patient receives the most appropriate priority for allocation. As part of our evaluation, we offer the following suggestions: With highly sensitized patients and minority groups, it is imperative to identify areas that will provide patients with greater opportunities to transplantation. Providing extra credit for existing HLA loci that patients have will be beneficial, and we appreciate that this will be looked at in organs as they move into the continuous distribution model. A potential risk that we can identify is that increased sensitization (especially in heart and liver) may lead to decreased acceptance of organ offers. Patients that are currently listed should be informed by their coordinators and physicians of any change in CPRA calculation and how it will benefit them. This should ideally occur in an office visit, so that all questions can be answered, and patient be fully informed on how this may potentially impact and benefit them. Prior to implementation, a one- or two-week time frame may not be sufficient. We propose that this timeframe be extended by a few weeks. This would allow those centers that are large, or who have not been currently listing these loci to go through their waitlist carefully to assure accurate documentation. Region 7 | 03/21/2022 Sentiment: 2 strongly support, 11 support, 3 neutral/abstain, 0 oppose, 0 strongly oppose. No comments. American Society for Histocompatibility and Immunogenetics | 03/19/2022 The American Society for Histocompatibility (ASHI) and its National Clinical Affairs Committee (NCAC) appreciate the opportunity to provide feedback regarding the proposed change to the CPRA calculation. ASHI strongly supports increasing the specificity of the current formula with the inclusion of a larger data set, additional loci, and allele-level antibody values. However, since many histocompatibility laboratories and transplant programs do not prioritize Anti-HLA DQA1, DPA1, and DPB1 antibodies when predicting transplant outcomes, many centers will need to re-evaluate their criteria for listing unacceptable antigens. Furthermore, the proposed transition time for acquiring documentation for CPRA 99-100% candidates may not be sufficient; this time frame should be extended to allow for centers to account for the anticipated impact on their candidates’ CPRA and prioritization for allocation. ASHI additionally is in support of allowing CPRA to be viewable for all candidates (heart, lung, kidney, and pancreas), independent of its use for allocation. This allowance may offer additional guidance, specifically as it relates to the criteria utilized for listing unacceptable antigens for additional organ groups. Region 1 | 03/18/2022 Sentiment: 4 Strongly Support; 7 Support; 2 Neutral/Abstain; 0 Oppose; 0 Strongly Oppose. Comments: One attendee commented that the importance of this is partially based on the size of the circles used to allocate organs because in an area with a great deal of homogeneity, it could be a disadvantage if the circles get larger. Lung Transplantation Committee | 03/17/2022 The OPTN Lung Transplantation Committee appreciates the opportunity to provide feedback on the OPTN Histocompatibility Committee’s Change Calculated Panel Reactive Antibody (CPRA) Calculation proposal. The Committee noted that the lung community is currently under-reporting unacceptable antigens, but pointed out that this behavior may change due to the tradeoff of a candidate receiving CPRA points as part of their composite allocation (CAS) score as lung moves into continuous distribution or the program having the ability to entertain all offers for that candidate. The Committee supported this proposal overall, but expressed interest in including evaluation of a CPRA CAS points benefit versus considering all potential offers for a candidate as part of post-implementation monitoring. Region 9 | 03/17/2022 Sentiment: 3 strongly support, 8 support, 2 neutral/abstain, 0 oppose, 0 strongly oppose. No comments. American Society of Transplant Surgeons | 03/17/2022 The American Society of Transplant Surgeons is Neutral/Abstains. Attachment University of Pennsylvania | 03/17/2022 We applaud the Histocompatibility Committee for their efforts and leadership on this proposal. We support this proposal to revise and update the cPRA calculation and giving the options to transplant center to incorporate HLA-DQA1, DPA1, and DPB1 alleles in the cPRA calculation. We also support making cPRA viewable in a candidate’s registration for all organ types. We recommend extending the transition period, to allow transplant programs more time to ensure highly sensitized patients have appropriate priority. Anat Tambur | 03/14/2022 While this is a step in the right direction, there are significant omissions in this proposal. The most critical one is the presentation of HLA-DQ antibodies as the alpha/beta heterodimers. The antibody specificities, as obtained directly from the SAB assay is at the heterodimer format so there should be no barrier to using those. The frequency information obtained from the NMDP can be presented as the alpha/beta heterodimers as they have genotype frequencies. By restricting the presentation to the individual DQ chains, significant level of information is missed as we have demonstrated in several publications. It disadvantage patients by either not providing them with the proportional allocation points, or by having to block what is in fact compatible donors, Anonymous | 03/14/2022 I applaud the Histocompatibility Committee for their efforts and leadership on this proposal. I support this proposal to revise and update the cPRA calculation and giving the options to transplant center to incorporate HLA-DQA1, and DPB1 alleles in the cPRA calculation. I also support making cPRA viewable in a candidate’s registration for all organ types. I recommend extending the transition period, to allow transplant programs more time to ensure highly sensitized patients have appropriate priority. American Nephrology Nurses Association (ANNA) | 03/11/2022 ANNA supports. Attachment STEVEN GEIER | 03/10/2022 This proposal is excellent, it will greatly improve the current CPRA calculator by addressing many inequities, and we will no longer have to use the Canadian calculator. Thank you on behalf of our transplant patients, programs and HLA labs, for the years of careful work, planning, and validations by the Histocompatibility Committee with the help of many UNOS specialists, to improve the our CPRA! Kidney Transplantation Committee | 03/08/2022 The OPTN Kidney Committee thanks the Histocompatibility Committee for their efforts on this proposal. The Kidney Committee supports this proposal to revise and update the cPRA calculation. The Committee also supports making cPRA viewable in a candidate’s registration for all organ types. Several Committee members recommended extending the transition period, to allow transplant programs more time to ensure highly sensitized patients have appropriate priority. Minority Affairs Committee | 03/04/2022 The OPTN Minority Affairs Committee appreciates the opportunity to comment on Change Calculated Panel Reactive Antibody (CPRA) Calculation. The Minority Affairs Committee supports CPRA data being viewable to all candidates, as this will provide additional information when a program assigns unacceptable antigens for non- renal candidates. The Committee also favors a transition time longer than one week for kidney programs to obtain documentation for allocation priority for CPRA 99-100% candidates. Region 3 | 03/02/2022 • Sentiment: 8 strongly support, 9 support, 0 neutral/abstain, 0 oppose, 0 strongly oppose • Comments: Specificity entry into new calculator should be modified to make it easier to enter multiple specificities for high PRA patients. Sam Zhang | 03/01/2022 I support the proposal in general and appreciate the effort of the committee in developing the new algorithm for CPRA calculation. The HLA typing data used in the current CPRA calculator need to be updated. The inclusion of HLA-DPA1/DPB1/DQA1 in the proposed CPRA calculator gives transplant centers a choice to enter these avoids and get CPRA points. I have some comments: 1. Many centers don’t enter DPB1 antibodies, even DQA1 antibodies as avoids. One of the reasons is that entering these antibodies as avoids do not change CPRA points. This new CPRA calculation proposal will likely change centers’ behavior in future. It would be interesting to monitor if this behavior change affects the rate of donor offer. 2. There are about 1000 HLA-DPB1 alleles that can be potentially detected in the bone marrow donors, but only the small number of DPB1 alleles are included in the commercially available antibody tests. I am wondering if the DPB1 alleles that are not included in the single antigen bead test, are used in the proposed CPRA calculation. 3. I checked DP antibodies in patients on our center’s waiting list and found that the more Caucasian patients have DP antibodies than African American patients and Hispanic patients, suggesting this new CPRA calculator may not benefit African American patients on the waiting list. But this is only from our center’s data, other centers may have different patient populations. University of Rochester | 02/24/2022 We support this initiative and appreciate the effort of the committee in developing the plan. The current calculator is woefully outdated. The webinar provided by the committee leadership was very helpful and answered our questions. While we acknowledge that data remains incomplete regarding some allele level antibodies and those detected against HLA-DP, transplant centers vary in the acceptance of risk and this proposal allows centers to define that for themselves and their patients. As to the input the committee requested for other items: 1. we believe 1-2 weeks will be sufficient notice to complete documentation for our patients, and 2. CPRA should be viewable for all candidates; we find this to be an issue, especially for the cardiac transplant population. The clinicians need to see it. Region 8 | 02/23/2022 5 strongly support, 11 support, 2 neutral/abstain, 0 oppose, 0 strongly oppose - Region 8 supported this proposal. A member explained that his institution supports the general idea of an improved and more accurate cPRA calculation. He pointed out that in pediatric heart transplant, sensitization does not impact priority status, however sensitization does play a big role in transplant eligibility and decision-making regarding desensitization. The member suggested that it would be interesting to know how this change could impact candidacy. A member commented that the cohort data definitely needs to be updated. Michael Gautreaux | 02/22/2022 I strongly support this proposal. For far too long HLA laboratories have been able to detect allele-specific antibodies in sensitized patients. We have not been able to effectively use these specificities to narrow down the list of compatible donors. Nor have we been able to fully account for all specificities that a recipient may have which could greatly affect their ability to get an offer from a particular donor. Far too often it takes a virtual assessment or virtual crossmatch to rule a possible donor in or out. As we move further to virtual assessments and crossmatches, this could be vitally important. Region 4 | 02/18/2022 5 strongly support, 20 support, 1 neutral/abstain, 0 oppose, 0 strongly oppose - Region 4 supported the proposal and one attendee commented that CPRA should be weighted in a non-linear point system in allocation. Points for highly sensitized patients should be reworked to give priority to those that need it (different points for 99.5 vs 99.9). Falyn York | 02/16/2022 I am an undergraduate student with a very green sense of organ transplantation and the complex science surrounding it. I am taking immunology which gives me some familiarity with antibodies, HLA, etc, but I am no expert. Upon listening to the proposal and reading some of the comments made, I feel conflicted by the proposal. It is meant to increase testing for sensitivities in patients that is not currently used in the CPRA. I believe this means that highly sensitized patients will now have more testing to assess their sensitivities and thus allow for more precise matching of organs to recipients. I think that when it comes to any complex matching system, you have to assess what is the appropriate scope of the match. We can test for 1 sensitivity to all the million possible differences that could lead to a less than perfect match. What really matters is the % match necessary to be successful. Will these proposed additional markers make enough of a difference between successful transplantation and rejection to warrant their widespread integration? Overall I think it would be beneficial to have more data than less, and thus support the proposal of new CPRA including data from more ethnic groups. I just question whether or not it has been determined that the benefits of this increased sensitivity testing would outweigh the decrease in potential donors patients have. Additionally, I do not see why expanding from kidneys only to all organ donations would be harmful to patients and their matching process, so I support this notion. However, I believe transplant organizations would need more than 1 week to implement this system. Any kind of organization would need more than 1 week to do anything, as these are large entities and progress takes time to diffuse. Region 5 | 02/16/2022 9 Strongly Support, 19 Support, 3 Neutral/Abstain, 2 Oppose, 0 Strongly Oppose - A member commented that for the cPRA calculator update her institution believes that a one-week transition time is too short, especially for large transplant centers. For patients that do not have enough wait time and have low cPRA, these patients are usually not ready for transplant. Her institution supports a minimum of 2 months transition time and they want to see cPRA of heart, lung and liver patients, but don’t want the UAg to block donors for certain cases. Another institution supports the proposal and noted that this proposal allows the possibility to more accurately estimate cPRA, including some new antigens, like DP, is overdue. Further, they have patients that would be >70%cPRA but listed as 0% because DP is not included in the current calculator. This new calculator is relying on a much larger data set, which they have already began using at their institution. A member supports this policy that promotes transplantation of highly sensitized patients but expressed a concern if tightening the criteria limits the patients’ access by making the criteria too stringent. A member institution commented that they are generally supportive of making more detailed cPRA definitions, however they disagree with one detail regarding DP alleles and including them in the cPRA calculation. A member commented that it is not clear that adding DQA1, DPA1, and DPB1 antibody targets in the CPRA calculation will substantially improve matching. Further it may impair matching of a suitable donor with broadly sensitized candidates, thereby reducing matching efficiency and potentially decreasing the number of transplants. Region 10 | 02/16/2022 6 Strongly Support, 9 Support, 1 Neutral/Abstain, 0 Oppose, 0 Strongly Oppose Rajalingam Raja | 02/02/2022 As an HLA laboratory director, I do not support this proposal, mainly on adding DQA1, DPA1, and DPB1 antibody targets in the CPRA calculation. I have the following rationales: 1). DPA1/DPB1 antibodies do not bind cells to cause positive flow cytometry crossmatch unless they are strong with over 7,000 MFI; 2). The impact of DPA1/DPB1 antibodies on transplant outcomes is not well documented. In fact, several transplant centers, including us at UCSF, transplant kidneys with preformed donor-specific DPB1/DPA1 antibodies without compromising the transplant outcomes; 3). Anti-DPB1 antibodies are frequent in highly sensitized candidates. Over 52% of waitlist candidates with 100% CPRA (current value) are frequently sensitized to all other HLA loci (i.e., HLA-A, B, C, DRB1, DRB3/4/5, DQB1), make HLA-DPB1 antibodies. Adding additional unacceptable DPB1 antigens for the broadly sensitized candidates will impair the chances of finding a compatible donor. Currently, only ~10% of those with 99-100% CPRA receive a deceased donor kidney transplant despite high priority points and broader sharing (national level sharing for 100% CPRA patients). Adding clinically irrelevant DPB1 antigens as unacceptable antigens for those with 100% CPRA will stop them from receiving any kidney offer. Anonymous | 02/01/2022 As a laboratory professional I strongly support the change in CPRA calculation. The change is long overdue, and effectively rectifies the few glaring holes in the old system, and permits meaningful use of intermediate resolution typing of donors. Anonymous | 01/27/2022 I support parts of this proposal. Without fully understanding the algorithm you currently use, and without a physician level / transplant center depth of understanding I can only address parts of this proposal. 1. I know many people who became highly sensitized through no fault of their own, including all three categories, blood transfusion, pregnancy and previous transplant. The highly sensitized candidates have lost out on opportunities for transplant for decades, and many have died. This is unfair and needs to be balanced to give them (and us) a fair shake. As for pooling all organs, I would rather limit it to specific organs, and keep it a kidney only category. But, I would have to defer to my nephrology team at Sutter CPMC and my surgeon to make that determination. Thank you.