OPTN Kidney Paired Donation (KPD) Histocompatibility Testing Policies Kidney Transplantation Committee Spring 2014

Background Kidney Committee distributed KPD policies for public comment in March 2012 A number of commenters had concern with histo section due to missing requirements Professional societies brought together a KPD consensus conference around same time This proposal incorporates spring 2012 OPTN public comment feedback findings from KPD consensus conference recommendations from OPTN Histo Committee Let me start off by giving you some background on this proposal. Currently, the OPTN KPD program is a pilot. As the Kidney Committee moves to make it a permanent program, many of the requirements in the Operational Guidelines are being proposed as OPTN policies. In March 2012, the Committee distributed a proposal converting sections of the Operational Guidelines into policy. Among them were proposed policies governing histocompatibility testing in the OPTN KPD program. The majority of the March 2012 proposal received support, but there were a number of comments pertaining to the histocompatibility policy sections missing critical elements. The Committee opted to reserve the histo section and formed a Histocompatibility Advisory Committee (HAC) to recommend how the policy proposal should be amended.   Around the same time, a number of professional transplant societies convened a KPD consensus conference. The recommendations in this proposal reflect those that came out of the Histo Advisory Committee and incorporate feedback received during the spring 2012 public comment period, the 2012 KPD consensus conference findings, and the OPTN/UNOS Histocompatibility Committee.

The Problem Low match success rate in KPD program Antibody related issues and positive crossmatches continue to account for a number of match failures Insufficient histocompatibility testing requirements to prevent match failure While the OPTN KPD program has made great strides, the match success rate in the program still remains low. Matches can fail for a variety of reasons, but we know that a number of our matches fail due to antibody related issues and unexpected positive crossmatches. And, obviously, the consequences are great when a chain breaks and the donors and candidates end up missing out on a subsequent match run and additional transplant opportunities. Data provided to the KPD Workgroup show that 52% of failed matches were not actually refused, but did not proceed to transplant due to refusals of other matches in the same exchange. Of the matches through mid-April 2013 that were refused, 30% were refused due to either “positive crossmatch” or “unacceptable antigens.” An analysis of data through September 30, 2013 showed that crossmatch or antibody-related issues continue to account for approximately 30% of refusal reasons. Of the crossmatch-related refusals, about 1/3 were due to an actual positive crossmatch, while 2/3 were due to unacceptable antigens. This proposal seeks to put in place histo testing policies that will help prevent some future match failures.

Goal of the Proposal Increase match success rate in KPD program by preventing unexpected positive crossmatches that can break chains and prevent candidates and donors from accessing subsequent match runs and transplant opportunities Promote transplant safety through more effective screening of kidney offers The goal of the changes is to increase the match success rate in the OPTN KPD program by preventing unexpected positive crossmatches and refusals due to incomplete histocompatibility testing and information. The proposal is also intended to increase safety in the KPD program through more effective screening on kidney offers in the program.

Proposed: HLA Typing Molecular HLA typing required for donors and candidates Loci required for donors: HLA-A, B, Bw4, Bw6, C, DR, DR51, DR52, DR53, DPB, DQA, DQB Loci required for candidates: HLA-A, B, Bw4, Bw6, DR If candidate has unacceptable antigens, additional loci required: C, DR51, DR52, DR53, DPB, DQA, DQB Candidate’s hospital must retype donor to confirm HLA type The first piece of this proposal deals with HLA typing requirements. The proposal includes a requirement for donors and candidates to be typed using molecular methods. This was a recommendation from our Histo Advisory Committee since molecular typing is a much superior method in determining compatibility. It was also one of the findings from the KPD Consensus Conference. Molecular typing is currently required on all deceased kidney donors as well. It is not currently required for candidates on the waiting list for a deceased donor kidney. Under the proposal, a full list of HLA loci is required for donors. This list is more expansive than what was proposed previously. We received a number of comments that the previous list was missing certain loci (DQA and DPB) needed for making decisions about donor acceptance. This list is also consistent with what the Histo Committee is proposing for deceased donors. Many of the public comments also suggested that candidates with antibodies to certain types need to have additional HLA information reported. So, we included this in the proposal. Finally, the candidate’s hospital is required to retype the donor to confirm the donor’s HLA type before transplant.

Proposed: Antibody Screenings Candidate’s transplant hospital must screen for antibodies at all of the following times: every 90 days when potentially sensitizing event occurs if candidate reactivated after more than 90 inactive days if unacceptable positive crossmatch occurs that prevents transplant with matched donor Labs must use method at least as sensitive as crossmatch method Physician/surgeon (or designee) and lab director (or designee) must review and confirm UA’s listed for candidate There are new antibody screening requirements as well. Our Histo Advisory group recommended that hospitals screen candidates for antibodies every 90 days, when a potentially sensitizing event occurs, if the candidate is reactivated after having been inactive for more than 90 days, and in case where a candidate and donor have been matched and there is an unacceptable positive crossmatch that prevents a transplant (and therefore contributes to match failure). Several of these screening time periods are recommended by the findings in the KPD Consensus Conference. When performing antibody screenings, labs would be required to use a method that is at least as sensitive as their crossmatching method (a recommendation from ASHI). And, the candidate’s physician or surgeon (or designee) and the histocompatibility laboratory director (or designee) must review and confirm the unacceptable antigens listed for the candidate. This again goes toward preventing refusals later in the match process because of unacceptable antigens. It is also based on a recommendation in the KPD consensus conference findings that physicians and histo lab personnel should have regular communication on candidates in a KPD exchange. This is also consistent with a requirement in the new KAS pertaining to patients with CPRA at or above 99%.

Proposed: Crossmatching Candidate’s transplant hospital must perform physical crossmatch before donor’s nephrectomy is scheduled Must report crossmatch results to donor’s transplant hospital and UNOS If unacceptable positive crossmatch occurs between candidate and matched donor, candidate’s hospital must inactivate candidate before next match run, review the unacceptable antigens (UA), and report reason to UNOS w/in 7 days Candidate can be reactivated once review and update (if applicable) of UAs is complete Finally, the proposal contains new crossmatching requirements. The original public comment proposal required the candidate’s hospital to perform a preliminary crossmatch before the matched donor’s recovery procedure. Several public comments pointed out that the crossmatch would need to be performed earlier in order to avoid match failure later in the process. In addition, federal regulations require histocompatibility laboratories to perform a final crossmatch and have the results available before a kidney transplant. The proposal specifies that the candidate’s transplant hospital is responsible for performing a physical crossmatch before the donor’s nephrectomy is scheduled. The candidate’s hospital must report the results to the OPTN Contractor and the matched donor’s transplant hospital. In addition, the proposal would require that a candidate’s hospital inactivate a candidate prior to before the next match run if an unacceptable positive crossmatch occurs between a matched pair that prevents transplant. The physician/surgeon and histo lab director must review the unacceptable antigens listed and the hospital must report the reason for the positive crossmatch to UNOS within 7 days.

Supporting Evidence Crossmatch-related refusals (postive crossmatch or unacceptable antigens) account for ~30% of failed matches 61 programs had accepted at least one match offer for which the entire exchange fell through Some programs may have had a disproportionately high number of crossmatch-related refusals 39 programs refused at least one match offer due to a crossmatch-related reason As I’ve mentioned earlier, crossmatch or antibody-related issues account for approximately 30% of refusal reasons. In match runs through June 3, 2013, 61 transplant programs had accepted at least one match offer for which the entire exchange subsequently fell through. Some programs had more than 20 such futile acceptances Some programs may have had a disproportionately high number of crossmatch-related refusals : Seven programs receiving at least 10 offers had refused more than half of them. One program refused 19 matches due to crossmatch-related reasons. For one other program, 4 of 5 (80%) refusals were due to crossmatch-related reasons. However, this problem is not isolated to a few institutions: 39 programs refused at least one match offer due to a crossmatch related reason.

Specific Feedback Request If unacceptable positive crossmatch occurs between candidate and matched donor, candidate’s hospital must inactivate candidate in the KPD program before next match run If this change is approved, is it less burdensome for transplant programs if the inactivation is automatic (completed by UNOS)? The Committee would like specific feedback on a couple of the proposed changes. There was significant discussion about whether it would be incredibly burdensome to KPD programs to inactivate and then reactivate their candidates in cases where an unacceptable crossmach breaks a chain and the candidate’s info must be updated. Some members thought it would less burdensome if UNOS automatically inactivated the candidate and reactivated once the review is complete. Other members thought this would make it more burdensome and that it would be easier for the program to do this on their own. This is something the committee is looking for particular feedback on.

Specific Feedback Request Is it burdensome to require antibody screenings every 90 days for ALL candidates (even if not sensitized?) Should longer timeframe between screenings apply for non-sensitized candidates? 180 days? The Committee would like specific feedback on the proposed change I just explained. There was significant discussion about whether it is overly burdensome to require antibody screenings every 90 days for all candidates. Some workgroup or committee members have suggested that the requirement should be more relaxed for non-sensitized candidates. The Committee did discuss possibly making antibody screenings required every 180 days for non-sensitized candidates. We’d like to get your input on this.

What Members will Need to Do Donor’s transplant hospital responsible for reporting donor HLA info, arranging shipment of donor blood sample to candidate’s hospital or histo lab Candidate’s transplant hospital responsible for reporting candidate HLA info, confirming donor HLA info, antibody screening requirements, crossmatching requirements If this proposal is approved, the OPTN KPD donor hospital will be responsible for reporting the required HLA information on the donor, as well as arranging shipment of the donor’s blood sample to the candidate’s hospital or affiliated histo lab. The OPTN KPD candidate hospital will be responsible for reporting the candidate’s HLA information, confirming the donor’s HLA information, meeting all antibody screening requirements, as well as the crossmatching requirements.

Questions? Mark Aeder, MD KPD Work Group Chair mark.aeder@uhhospitals.org Name Region # representative Email Gena Boyle Committee Liaison gena.boyle@unos.org