Why HLA-DQ?

As demonstrated in the previous sections, the true nature of HLA-DQ antibody specificities does not categorize well into the 7 serotypes that are currently recognized. Reporting these antibodies at the serological level masks a patient’s true level of HLA-DQ sensitization and can even appear as though the patient possesses antibodies against their own typing. Nevertheless, DQ antibodies are still routinely reported using this nomenclature. Although it is possible to enter DQα or DQβ allelic specificities into UNet, only unacceptable antigens (UA) that are assigned at the serological level are considered when calculating cPRA and priority points. This inevitably leads to several detrimental consequences and does not allow for a fair and equitable organ allocation system.

The question arises, then: why must we still assign DQ unacceptable antigens at the serological level?

UA entered into UNet are used to determine the calculated Panel Reactive Antibodies (cPRA), a measure of sensitization for kidney and pancreas transplant patients, and allocation points, which affect a patient’s priority within the waitlist. The introduction of cPRA was an advancement that assured accountability by the centers entering the data – if a patient is listed as having antibodies to certain HLA antigens, they are automatically excluded from being considered a potential recipient for donors with this antigen.  The calculator that is used to determine these measurements was developed in the late 2000’s, when the importance of allele-level differences was not yet fully appreciated. Moreover, the field had referred to HLA-DQ alleles mostly at the level of HLA-DQB1, not taking into consideration the significance of the different HLA-DQA1 that is combined with it. As a result, the pool of deceased donors that was used to determine HLA frequencies was not high-resolution typed at all loci. Without allele-level typing information on DQ, population frequencies of the DQ alleles cannot be determined, which means that a cPRA using allelic UA cannot be calculated. Until a new frequency database is developed using high-resolution donor typing information, we are left with entering DQ UA at the serological level.

We can now discuss the implications of this outdated system, and why we feel it is so important to develop a new cPRA calculator or methodology that better reflects a patient’s true level of sensitization.

As we just mentioned, because the current cPRA calculator was developed using DQ frequencies that were typed at the serologic level, DQ UA must also be assigned at serologic level in order to be factored into cPRA and allocation point calculations. In order to illustrate the heterogeneity of allele frequencies within the DQ serotypes, we typed 1,591 living donor candidates from our center using molecular methods to obtain 3,182 high-resolution HLA-DRB1-DQA1-DQB1 haplotypes (these individuals had sufficient family related information to make those haplotype assignments). The allelic frequencies for each serotype are shown below.

Taking DQ2 as an example, a patient possessing strong antibodies against DQA1*05:01/DQB1*02:01, but not against DQA1*02:01/DQB1*02:02 (or DQA1*03:01G/DQB1*02:02) would theoretically only be incompatible with roughly 45% of DQ2 donors (based on our study’s population frequencies). However, entering DQ2 into the current UNOS calculator does not account for this, resulting in an overestimation of the patient’s true sensitization level.

Similarly, if we are to take another example using DQ7, a patient possessing antibodies against DQA1*03:01G/DQB1*03:01 and DQA1*02:01/DQB1*03:01 would be incompatible with only 20% of all DQ7 donors. Entering DQ7 as unacceptable in UNOS would again overestimate this patient’s cPRA. Furthermore, this would block not only DQA1*03:01G/DQB1*03:01 and DQA1*02:01/DQB1*03:01 donors, but all other DQ7 donors as well, the majority of which would have likely resulted in a negative crossmatch. In this scenario, the patient would have never received offers for these potentially compatible donors, precluding them from an immunologically acceptable transplant.

To quantify just how many waitlist patients this actually affects, we performed a retrospective analysis of all crossmatches that were performed in 2011 by our center’s organ procurement organization. It is important to appreciate that given our perspective on the subject, our center did not list DQ UA unless there was positive reactivity against the full allelic family. Of the 1130 crossmatches that were performed, 147 contained DSA against the donor’s serologic DQ typing. 112/147 resulted in positive crossmatches; however, the remaining 35/147 crossmatches were negative despite serologic HLA-DQ DSA. For those patients, the serologic DSA had different allelic specificities than the donor’s typing. None of the 147 crossmatches would have been performed if the DQ-DSA had been listed serologically as UA, yet in this small cohort, nearly one-quarter of the patients with serologic DQ DSA were compatible with their donor offer and were likely able to proceed with transplantation.

Although DQ UA must be assigned into UNet at the serological level in order to contribute toward cPRA and allocation point calculations, it is still possible to enter them at allele-level, though not as αꞵ combinations. While this is useful for blocking donors with those specificities, it does not affect that patient’s cPRA, nor does it award them additional allocation points.

For patients that display antibody profiles like the two examples above, transplant centers are left with making a difficult choice:

1) Assign UA at allele-level to receive offers from potential compatible donors within that serotype while missing out on priority points, or

2) Assign UA at serologic-level in order to gain additional priority points, but miss out on potential compatible donors.

It’s a double-edged sword and it has no place in a truly equitable allocation system.

To show just how important this choice can be, we need to look into the two main results that are impacted by the decision: cPRA (and corresponding allocation points), and potential compatible donors. In collaboration with our colleagues in Paris, our study in 2017 investigated this using high-resolution haplotypes of 1,166 donors and antibody specificities of 2,075 kidney waitlist candidates who had at least one HLA-DQ antibody. cPRA and number of potential compatible donors were determined using the haplotype frequencies of the cohort (calculated based on 2 years’ worth of effective donors for that population). In order to determine the impact that DQ had on cPRA and potential compatible donors, two analyses were performed using either serologic or allelic DQαꞵ combinations. The remaining loci were kept at low-resolution.  The overall data can be summarized by the two figures below.

As the two figures demonstrate, the largest median change for both calculations occurred in patients between a serologic cPRA of 30-49%. Putting this into the context of allocation points, however, paints a different, more clinically relevant, picture.

The current Kidney Allocation System (KAS) imposes a sliding scale for allocating points, where the amount of points assigned increases exponentially as cPRA approaches 100%. This means that small changes in cPRA for the most highly sensitized patients will translate into the largest changes in allocation points. For example, patients with a cPRA of 100% currently receive 202 points according to the KAS sliding scale, while those with a cPRA of 99% receive 50 points, and those with a cPRA of 98% receive 24 points. Based on the results of our study, 37% of the patients who were assigned a serologic cPRA of 100% dropped to a lower cPRA after adjusting to allelic DQ assignment, translating to a decrease of at least 152 allocation points for each of these patients.

Interestingly, the observed increase in potential compatible donors was not equivalent among all blood types. Those with blood types O and A saw much more marked increases in number of potential compatible donors, while those with types B and AB saw smaller increases.

Figure: Increase in potential compatible donors when changing from serologic to allelic DQ assignment by blood type

Source: Tambur AR, Audry B, Antoine C, Suberbielle C, Glotz D, Jacquelinet C. 2017. Harnessing scientific and technological advances to improve equity in kidney allocation policies. Am J Transplant 17:3149-3158.

The new KAS was instrumental in improving equity of organ access to highly sensitized waitlist patients as well as other disadvantaged groups. However, we believe that more can be done to continuously improve accessibility and equity. This may include reevaluating how HLA-DQ antigens and antibodies are reported and incorporated into our current allocation policies.