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Require Human Leukocyte Antigen (HLA) Confirmatory Typing for Deceased Donors

eye iconAt a glance

Current policy

Current policy requires that histocompatibility labs perform Human Leukocyte Antigen (HLA) typing on deceased kidney and pancreas donors to make sure the recipient and the organ are compatible. This is required for all other organs upon request of the transplant hospital. However, there can be rare instances where the test results are incorrect due to assay or laboratory error and the recipient and the organ are not compatible. The Histocompatibility Committee proposes requiring labs to perform two HLA typing tests on deceased donors to help prevent these errors.

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Proposed changes

  • Require labs to perform two HLA typings from deceased donors.
    • The two tests must be drawn from two different samples, at two different times.
  • The lab must provide the results of these tests according to the terms in their contract with the OPO.

Anticipated impact

  • What it's expected to do
    • Improve transplant recipient safety by ensuring they are receiving a compatible organ
    • Improve transplant recipient outcomes by preventing the need for an immediate second transplant due to the first transplant being incompatible
  • What it won't do
    • There are no changes for which organs HLA typing is required
    • There are no changes for the timing of the required HLA typings

Terms to know

  • Human leukocyte antigen (HLA): Proteins on the cell surface that differentiate between self and non-self.
  • 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.
  • Histocompatibility Laboratory: A member of the OPTN. A lab that performs immunologic testing, including but not limited to, Human Leukocyte Antigen (HLA) typing, antibody screening, or crossmatching, and serves at least one transplant hospital member or OPO.
  • Deceased donors: An individual from whom at least one organ is recovered for the purpose of transplantation after declaration of death.

Click here to search the OPTN glossary

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UCSF Immunogenetics and Transplantation Laboratory, Director: Dr. Rajalingam Raja | 02/03/2023

I direct the HLA lab at the University of California San Francisco (UCSF), which performs human leukocyte antigen (HLA) typing for ~500 local deceased donors annually. UCSF HLA lab strongly supports this proposal because of the following reasons. However, the proposal must include a condition demanding the use of two different test methods (e.g., RT-PCR, rSSO, SSP, Nanopore) or similar test methods from two different vendors to HLA type samples drawn at two separate times. 1. The HLA genes are incredibly polymorphic, with >35,820 alleles officially recognized per February 2023. Typing deceased donors for ever-increasing alleles of all 11 HLA genes within a short turnaround time is particularly challenging. 2. Currently used deceased donor HLA typing methods employ multiplexed PCR amplifications designed on the available sequence database, which is well-known for allelic dropouts and ambiguous results yielding erroneous typing. 3. Erroneous HLA typing of deceased organ donors can have profound patient safety implications, such as recipient death and unexpected hyperacute/ accelerated graft rejection. 4. Incorrect HLA typing can also cause inefficiencies in the OPTN/UNOS organ allocation system, such as 1) an increased cold ischemia time while HLA types are confirmed by repeat testing, 2) discards of organs shipped to far areas with incorrect HLA typing, and 3) possibly missed transplant opportunities for other candidates who may have been screened off of a match run because of incorrect HLA typing. 5. Comprehensive and precise HLA typing of deceased donors is crucial for precise virtual crossmatching to increase broader organ sharing across greater geographical distances. 6. Adopting a dual typing system for deceased donors will entail additional costs on reagents, but technologist time spent on deceased donor workup will not substantially change. Indeed, double typing will save the technologist time because of the more straightforward crosschecking between two typing assignments and eliminating repeat testing due to failures in certain wells or reflex testing to resolve ambiguities emerging from the single method. Furthermore, the recipient transplant hospital may discontinue repeating HLA typing of the imported donors in their local HLA laboratory if the original typing used for the allocation match run was attained by mandated dual typing. Therefore, the benefits far outweigh the increase in cost, if any. 7. Our recent research on this line concludes that the concurrent typing of two separate samples using two independent methods is ideal for obtaining accurate HLA typing of deceased donors within a short turnaround time, which is crucial for accurate virtual crossmatching for broader sharing (Reference: Cruz TD, Dames C, Pagaduan L, Cho Y, Kong D, Rajalingam R. Concurrent use of two independent methods prevents erroneous HLA typing of deceased organ donors - An important strategy for patient safety and accurate virtual crossmatching for broader sharing. Hum Immunol. 2022, 83:458-466).

Anonymous | 02/02/2023

I support this but only if the typing centers are able to do this . Adding an extra typing for deceased donors may require more equipment and staff. Having worked at a typing center and a non-typing center laboratory, there is a huge difference in the amount of work involved when typing is added to a deceased donor workup. We run the risk of laboratories dropping deceased donor typing if they cannot be reimbursed for the material and staffing cost of the confirmatory typing. What is most helpful with Deceased Donor typing is the availability of the Raw Data of the assay and not just a coversheet summary.

Anonymous | 01/27/2023

Most of the HLA typing errors are clerical, which could be avoided if a second set of eyes looks at the results and makes sure that the entry is correct. Also repeating the same typing with the same technology I don’t think solves anything. In the few cases that typing is “wrong” due to technology limitations, you would have the same wrong result twice. No all the labs have more than one molecular technology for HLA typing, and the ones that do, usually used technology that due to timing would not be suitable for deceased donor typing on call. Nanopore is promising but is not easy to do in the middle of the night while doing other HLA typings and crossmatches.

Valia Bravo-Egana | 01/26/2023

Statistics on low incidence of discrepancies on donor HLA typing are important to understand the magnitude of the problem. However, it should not be a justification to accept less than optimal outcomes. Even if only one patient is impacted by this situation, it should be enough to prompt our community to provide a meaningful answer, if available. In this case, implementing confirmatory donor typing as a safeguard to avoid the potential devastating consequences of typing mistakes seems to be reasonable and proportionate to the seriousness of the consequences of not doing it. This seems even more important these days, when organ allocation is not limited to regions but done nationally. Therefore, typing mistakes may have major implications in proper organ allocation. Furthermore, with the everyday increasing rates of usage of virtual immunological assessments, the accuracy of HLA typing becomes vital to provide this service. Finally, I strongly belief that patient safety is never enough. It is our responsibility to improve it and optimize it in an asymptotic manner, where we get closer and closer to the ideal but never get complacent and stop improvement. We own this to our patients and community.

Anonymous | 01/25/2023

This appears to be an rare problem with a disproportionately broad solution. There doesn't appear to be anything preventing a lab from performing an additional typing on another sample currently. It would seem best for each lab to evaluate problem areas and implement solutions accordingly.

Maria Bettinotti | 01/24/2023

The lack of a policy that mandates HLA confirmatory typing of deceased donors constitutes a high risk to the safety of transplant recipients and to the efficient use of organs within the OPTN deceased donor allocation system. The deceased donor's HLA type is a key component of organ allocation:

•Unacceptable antigens are listed in UNet for HLA sensitized candidates on the waiting list so that incompatible candidates are excluded from a match run. An erroneous donor HLA typing may result in the inclusion on the match run of patients highly sensitized against the donor.

•Transplant centers perform virtual crossmatches comparing the HLA antibody profile from the potential recipient with the donor's HLA type to determine whether donor specific antibodies (DSA) are present for specificities not listed as unacceptable antigens. Immunological risk assessment that will guide acceptance or rejection of an organ offer and peri-transplant treatment depends on the accurate determination of candidate/donor mismatches and DSA and therefore on the availability of the correct HLA typing of the deceased donor.

•A transplant program may also specify the maximum number of mismatched antigens it will accept. The OPTN will only offer organs from deceased donors with mismatched antigens equal to or less than the maximum specified. An incorrect HLA typing may result in the OPTN unwittingly offering an organ from a donor with higher level of mismatches than requested.

Currently, the nationwide organ allocation system is based on the deceased donor's HLA typing obtained from one sample and performed only once by a single laboratory. There is no redundancy in the system to safeguard from possible errors such as sample switches, even though an incorrect HLA type in UNet may have devastating consequences. Transplantation of an incompatible imported kidney may be prevented by a physical prospective crossmatch or a confirmatory HLA typing performed by the laboratory supporting the transplant center. However, for imported hearts and lungs, crossmatches and confirmatory typings are usually performed retrospectively due to time limitations. Based on an erroneous HLA typing, an organ may be transplanted to a patient with high levels of circulating donor specific antibodies which can lead to hyperacute or accelerated rejection. Furthermore, even if an error in the deceased donor HLA typing is caught in time to prevent a catastrophic event, it will cause the nation-wide allocation system to be disrupted as organs that have already been shipped to transplant centers may not be used for the intended recipient.

In summary, a single HLA donor typing cannot be guaranteed to be correct. An erroneous donor HLA typing in UNet will disrupt the organ allocation system nationwide and may cause a catastrophic event. Current OPTN policies demand that the OPO must ensure that each deceased donor's blood type is determined by testing at least two donor blood samples prior to the match run. The donor's HLA type is as critical as ABO type to determine patient/ donor compatibility and OPTN policies should contain at least as many safeguards for HLA typing as they do for ABO blood group testing.

Anonymous | 01/23/2023

The proposed policy is far out of proportion to the problem it is trying to address. Although an incorrect donor HLA type could conceivably cause problems for a recipient, it is an extremely rare situation where it would actually help. The background for the policy references a 2022 article from UCSF, which states that they found four typing discrepancies out of 1487 donors, for a 0.27% discrepancy rate. But there were actually only three discrepant typings (the fourth case was just an unusual haplotype), and one of the three discrepancies involved a novel DPB1 allele which would be a problem regardless of whether confirmatory testing was performed (and should be dealt with by epitope analysis anyway when DPB1 types are present that are not on the antibody screening panel). For the two remaining cases, there's a 50% chance the wrong typing would occur in the original typing and a 50% chance the wrong typing would occur in the confirmatory typing. So the real frequency of confirmatory typing helping avoid a match run being executed with a wrong HLA type is 1 in 1487, or 0.07%. Unlike ABO typing discrepancies, where the natural occurrence of anti-A and anti-B antibodies is a substantial concern, the vast majority of recipients would be unaffected by an incorrect donor HLA type as most have no HLA antibodies (77% of transplant recipients in our center have no HLA antibodies). Even for recipients who do have HLA antibodies, an incorrect donor HLA type is unlikely to cross the recipient's HLA antibody specificities (an exact figure is difficult to predict, but a rough guess is that two-thirds of the time the incorrect type wouldn't be an issue).

Anonymous | 01/19/2023

I would not recommend two HLA Typings for the same dononr. Since HLA discrepancies occur in approximately 0.3% of deceased donor typings which is a low percentage, this can be avoided by Histocompatibility labs by adding more check points and improve the process to avoid switching samples which is better than increasing the workload and the price of HLA Typing.

Gerald Morris | 01/19/2023

The increasing reliance on virtual crossmatch for improving access via organ sharing requires high confidence for donor HLA genotyping results. This should be considered similar to ABO blood typing. While documented donor mistypings are a relatively infrequent event, they are potentially high impact events with the potential for requiring re-running the match run or even catastrophic clinical outcomes for multiple recipients. Current methods for donor HLA genotyping are fast, and performing typing on a second sample can be perfomed either simulataneously or in sequence with minimal impact on time to providing HLA typing. The increased costs are minimal when considered as a part of overall cost of transplantation. Implementing this proposal would have a significantly positive impact on patient safety, efficiency of organ allocation, and improving organ sharing.