Mainly, two tissue antigen systems are responsible for rejection reactions in allogeneic kidney transplantation: (1) the ABO blood group antigen system and (2) the highly polymorphic HLA antigen system with >17,000 currently known alleles. Both antigen systems have been part of the deceased donor kidney allocation systems, and recent data from the Collaborative Transplant Study, the United Network for Organ Sharing, and the Australia and New Zealand Dialysis and Transplant Registry indicate a continuing beneficial effect of HLA matching in organ transplantation (1–3).
Traditionally, six antigens from three different HLA gene loci (A, B, and DR) were considered for matching of donor/recipient pairs in kidney allocation algorithms, whereas antibodies are currently determined in the recipients’ sera before and after transplantation against antigens from 11 different HLA loci (A, B, C, DRB1, DRB3, DRB4, DRB5, DQA1, DQB1, DPA1, and DPB1). DQ antigens have not been part of the kidney allocation algorithms because of the high association of DR antigens with certain DQ antigens, a phenomenon called linkage disequilibrium. Because of this strong linkage, DR matching in many patients means automatically matching for DQ. In the meantime, the interest in DQ antigen matching increased, because in several studies, de novo donor-specific HLA antibody development during antibody-mediated rejection reactions was found to be directed frequently against HLA-DQ antigens (4).
In this issue of the Clinical Journal of the American Society of Nephrology, Leeaphorn et al. (5) report evidence that, in addition to HLA-A, -B, and -DR matching, matching for HLA-DQ antigens could also be beneficial in recipients of deceased as well as living donor kidneys regarding clinical outcome; >90,000 patients transplanted between 2005 and 2014 in the United States were analyzed. This high number was necessary, because the most important part of this analysis had to be performed in the subgroup of patients who received a zero DR and one DQ mismatched deceased donor organ; the number of such patients is, due to the strong linkage disequilibrium between HLA-DQ and HLA-DR and exclusion of recipients with cold ischemic time >17 hours, small.
The most frequently occurring associations between HLA-DR and HLA-DQ antigens are listed in Table 1. Also dependent on the analyzed population, if a recipient-donor pair is, for example, matched for the HLA-DR11 antigen, it will also be matched with a high probability for the HLA-DQ7 antigen. However, a donor HLA-DR7 antigen can be associated with either the HLA-DQ2 or the HLA-DQ9 antigen and represent a mismatch if the donor has the DR7/DQ2 and the recipient has the DR7/DQ9 constellation. By analyzing patients with zero DR/one DQ mismatches, Leeaphorn et al. (5) found that these patients had a higher rate of acute rejection episodes during the first year after transplantation and a higher rate of overall graft loss at 10 years than the patients with zero DR/zero DQ mismatches.
Table 1.
Most frequent HLA-DR/DQ associations (serologic nomenclature)
| DQ2 | DQ4 | DQ5 | DQ6 | DQ7 | DQ8 | DQ9 |
|---|---|---|---|---|---|---|
| DR7a,c | DR4a | DR1 | DR13a | DR4a | DR4a | DR7a |
| DR9a,b | DR8a | DR10 | DR15 | DR8a | DR9a | |
| DR17 | DR18 | DR14 | DR11 | |||
| DR16 | DR12 | |||||
| DR13a |
These DR antigens are also often associated with other DQ antigens. The association is common in African Americanb and Asianc population.
Unfortunately, there was no significant association between DQ mismatching and allograft outcomes in patients with >17 hours of cold ischemia time who made up more than one half of the deceased donor population. Furthermore, the lack of association with 1- or 2-year graft survival or with 10-year graft loss due to chronic allograft nephropathy limit the clinical applicability of these findings and diminish the enthusiasm about the reported findings. Should DQ matching then be applied only locally and in organizations, such as Eurotransplant, in which the majority of the organs are shared within such a timeframe?
Nevertheless, the authors addressed an important issue which is of great interest. It will be necessary to quantify the effect of an additional HLA-DQ matching compared with matching for the HLA loci A, B, and DR. This will stimulate further discussion on whether additional matching for DQ should be considered in the allocation of deceased donor kidneys.
Disclosures
None.
Footnotes
Published online ahead of print. Publication date available at www.cjasn.org.
See related article, “HLA-DQ Mismatching and Kidney Transplant Outcomes,” on pages 763–771.
References
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