Significance of HLA-DQ in kidney transplantation: time to reevaluate human leukocyte antigen–matching priorities to improve transplant outcomes? An expert review and recommendations
Authors: Anat R. Tambur, Vasilis Kosmoliaptsis, Frans H.J. Claas, Roslyn B. Mannon, Peter Nickerson, Maarten Naesens
Journal: Kidney International (2021)

The weight of human leukocyte antigen (HLA) matching in kidney allocation algorithms, especially in the United States, has been devalued in a stepwise manner, supported by the introduction of modern immunosuppression. The intent was further to reduce the observed ethnic/racial disparity, as data emerged associating HLA matching with decreased access to transplantation for African American patients. In recent years, it has been increasingly recognized that a leading cause of graft loss is chronic antibody-mediated rejection, attributed to the development of de novo antibodies against mismatched donor HLA expressed on the graft. These antibodies are most frequently against donor HLA-DQ molecules. Beyond their impact on graft survival, generation of de novo donor-specific HLA antibodies also leads to increased sensitization, as measured by panel-reactive antibody metrics. Consequently, access to transplantation for patients returning to the waitlist in need of a second transplant is compromised. Herein, we address the implications of reduced HLA matching policies in kidney allocation. We highlight the observed diminished outcome data, the significant financial burden, the long-term health consequences, and, more important, the unintended consequences. We further provide recommendations to examine the impact of donor-recipient HLA class II and specifically HLA-DQα1β1 mismatching, focusing on collection of appropriate data, application of creative simulation approaches, and reconsideration of best practices to reduce inequalities while optimizing patient outcomes. The weight of human leukocyte antigen (HLA) matching in kidney allocation algorithms, especially in the United States, has been devalued in a stepwise manner, supported by the introduction of modern immunosuppression. The intent was further to reduce the observed ethnic/racial disparity, as data emerged associating HLA matching with decreased access to transplantation for African American patients. In recent years, it has been increasingly recognized that a leading cause of graft loss is chronic antibody-mediated rejection, attributed to the development of de novo antibodies against mismatched donor HLA expressed on the graft. These antibodies are most frequently against donor HLA-DQ molecules. Beyond their impact on graft survival, generation of de novo donor-specific HLA antibodies also leads to increased sensitization, as measured by panel-reactive antibody metrics. Consequently, access to transplantation for patients returning to the waitlist in need of a second transplant is compromised. Herein, we address the implications of reduced HLA matching policies in kidney allocation. We highlight the observed diminished outcome data, the significant financial burden, the long-term health consequences, and, more important, the unintended consequences. We further provide recommendations to examine the impact of donor-recipient HLA class II and specifically HLA-DQα1β1 mismatching, focusing on collection of appropriate data, application of creative simulation approaches, and reconsideration of best practices to reduce inequalities while optimizing patient outcomes. Kidney transplantation is a standard-of-care treatment for patients with kidney failure, with >75,000 kidney transplants performed annually around the globe.1Ying T. Shi B. Kelly P.J. et al.Death after kidney transplantation: an analysis by era and time post-transplant.J Am Soc Nephrol. 2020; 31: 2887-2899Crossref PubMed Scopus (32) Google Scholar,2Jenssen T. Hartmann A. Post-transplant diabetes mellitus in patients with solid organ transplants.Nat Rev Endocrinol. 2019; 15: 172-188Crossref PubMed Scopus (88) Google Scholar Unfortunately, although kidney graft survival increased significantly over the years, many patients lose their life-saving transplant and face return to dialysis, and potentially the gift of another kidney transplant.3Schrezenmeier E. Lehner L.J. Merkel M. et al.What happens after graft loss? a large, long-term, single-center observation.Transpl Int. 2021; 34: 732-742Crossref PubMed Scopus (3) Google Scholar The shortage of kidneys for transplantation, the medical and financial ramifications associated with the need to treat allograft rejection, and the impact of immunosuppression and graft dysfunction/loss on patient quality of life all highlight an unmet need for improving kidney transplant outcomes that must be addressed. Herein, we highlight the case for better and alternative donor-recipient human leukocyte antigen (HLA) matching as a strategy for prolonging graft survival and discuss the hurdles and potential approaches to reach this goal.HLA matching and organ allocation policiesSubsequent to initial studies demonstrating the beneficial role of HLA matching in improving kidney allograft survival,4Terasaki P.I. Vredevoe D.L. Porter K.A. et al.Serotyping for homotransplantation, V: evaluation of a matching scheme.Transplantation. 1966; 4: 688-699Crossref PubMed Scopus (20) Google Scholar transplant-related agencies were established in both Europe (Eurotransplant) and the United States (South-Eastern Organ Procurement Foundation, later referred to as the Organ Procurement and Transplant Network [OPTN]). Their role was to facilitate and promote transplantation while supporting HLA matching as part of their allocation algorithms. Initial matching strategies focused on class I HLA-A and HLA-B antigens, with the later addition of HLA-DR. More important, no significant advances have since been made in the way HLA compatibility is incorporated into allocation policies, and HLA-A, HLA-B, and HLA-DR matching (aiming at 0-A, 0-B, and 0-DR mismatches) is still considered the gold standard for most allocation agencies.With the advent of modern immunosuppression, the relative emphasis on HLA matching declined. Nevertheless, HLA mismatching is still an independent predictor of graft outcome in both large single-center studies and registry analyses.5Shi X. Liu R. Xie X. et al.Effect of human leukocyte antigen mismatching on the outcomes of pediatric kidney transplantation: a systematic review and meta-analysis.Nephrol Dial Transplant. 2017; 32: 1939-1948Crossref PubMed Scopus (4) Google Scholar, 6Mumford L. Maxwell H. Ahmad N. et al.The impact of changing practice on improved outcomes of paediatric renal transplantation in the United Kingdom: a 25 years review.Transpl Int. 2019; 32: 751-761Crossref PubMed Scopus (17) Google Scholar, 7Ruck J.M. Jackson A.M. Massie A.B. et al.Temporal changes in the impact of HLA mismatching among pediatric kidney transplant recipients.Transplantation. 2019; 103: 1267-1271Crossref PubMed Scopus (7) Google Scholar, 8Takemoto S. Terasaki P.I. Cecka J.M. et al.Survival of nationally shared, HLA-matched kidney transplants from cadaveric donors: the UNOS Scientific Renal Transplant Registry.N Engl J Med. 1992; 327: 834-839Crossref PubMed Scopus (180) Google Scholar For example, Williams et al.9Williams R.C. Opelz G. McGarvey C.J. et al.The risk of transplant failure with HLA mismatch in first adult kidney allografts from deceased donors.Transplantation. 2016; 100: 1094-1102Crossref PubMed Scopus (94) Google Scholar demonstrated a significant linear relationship of hazard ratios between incremental HLA-A, HLA-B, and HLA-DR mismatches and allograft survival in a US cohort of 189,141 adult recipients of first kidney allografts from deceased donors, equivalent to 994,558 years of follow-up, with 13% to 64% higher risk of graft loss for transplants with 1 to 6 HLA mismatches. Similar data were reported by the Collaborative Transplant Study, even in the modern transplant era, highlighting the impact of HLA mismatching on transplant outcomes, including graft loss and immunosuppression-related morbidity and mortality.10Susal C. Opelz G. Current role of human leukocyte antigen matching in kidney transplantation.Curr Opin Organ Transplant. 2013; 18: 438-444Crossref PubMed Scopus (96) Google Scholar, 11Opelz G. Dohler B. Association of HLA mismatch with death with a functioning graft after kidney transplantation: a collaborative transplant study report.Am J Transplant. 2012; 12: 3031-3038Crossref PubMed Scopus (61) Google Scholar, 12Opelz G. Dohler B. Effect of human leukocyte antigen compatibility on kidney graft survival: comparative analysis of two decades.Transplantation. 2007; 84: 137-143Crossref PubMed Scopus (232) Google ScholarImplementation of HLA matching into allocation algorithms is achieved by providing priority points to patients. Donor and recipient demographics, geography, size of the population, and equity of access considerations, among other factors, also influence priority points. For instance, specific to HLA, the Eurotransplant emphasizes matching by allotting 400.00, 333.33, 267.67, 200.00, 133.33, 66.67, and 0.00 to 0, 1, 2, 3, 4, 5, and 6 HLA-A, HLA-B, and HLA-DR mismatches, respectively, in their allocation system (Eurotransplant Kidney Allocation System13Eurotransplant. Chapter 4 Kidney (ETKAS and ESP). Eurotransplant Manual–version 2021 March 16.https://www.eurotransplant.org/wp-content/uploads/2020/01/H4-Kidney-2021.1-March-2021.pdfDate accessed: April 1, 2021Google Scholar). For reference, each year of wait-time is equivalent to 33.3 points. A reverse tactic is utilized in Australia and New Zealand,14Ministry of Healthhttps://www.health.govt.nz/system/files/documents/pages/nrts-nz-kidney-allocation-scheme-march2020.pdfDate accessed: March 20, 2021Google Scholar which value the role of HLA matching by deducting points as the number of mismatches increases. Thus, in New Zealand, patients start with 6000 points and each HLA-DR mismatch eliminates 2200 points, with 900 and 800 points eliminated for each mismatch at the HLA-B and HLA-A loci, respectively.In the United States, concerns were raised in the late 1990s about disparities in access to transplantation and graft outcomes for African American patients. It was identified that HLA matching disadvantages African American patients because differences in the HLA makeup between transplant waitlist patients and organ donor populations led to comparatively higher organ offers to Caucasian ancestry recipients.15Roberts J.P. Wolfe R.A. Bragg-Gresham J.L. et al.Effect of changing the priority for HLA matching on the rates and outcomes of kidney transplantation in minority groups.N Engl J Med. 2004; 350: 545-551Crossref PubMed Scopus (119) Google Scholar Proposals to remove some HLA loci from the matching algorithm followed, and ultimately, the OPTN/United Network of Organ Sharing (UNOS) adopted policies to reduce the weight given to HLA matching in organ allocation algorithms in the United States. Consequently, the current kidney allocation system of UNOS16Friedewald J.J. Samana C.J. Kasiske B.L. et al.The kidney allocation system.Surg Clin North Am. 2013; 93: 1395-1406Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar assigns priority only for allocating 0 HLA-A, HLA-B, and HLA-DR mismatched organs to adult patients, with 1 or 2 points for 1 or 0 HLA-DR mismatch, respectively. Pediatric patients receive some additional priority (4 points for ages 0–10 years and 3 points for ages 11–17 years). For reference, 1 point in kidney allocation system is equivalent to 365 days on the waitlist.Three additional loci of the HLA system (HLA-C, HLA-DQ, and HLA-DP), which were identified following the initial implementation of allocation priority, are rarely included as part of the matching algorithm, nor as part of transplant outcome analysis. The French system had introduced HLA-DQ matching into its kidney allocation scheme in 2015, with differential emphasis on different loci. Thus, full matching for HLA-A and HLA-B loci receives 100 points; full matching for HLA-DR is allotted 400 points, and full matching for DQ adds 100 points.17Agence de la BiomédecineProcedures d'application des regles repartition et d'attribution des greffons preleves sur personne decedde.https://www.agence-biomedecine.fr/IMG/pdf/v25guide-regles-de-repartition.pdfDate accessed: June 1, 2021Google Scholar Of note, to the best of our knowledge, the British National Health System Blood and Transplant18National Health ServicePOL186/11 — Kidney transplantation: deceased donor organ allocation.https://nhsbtdbe.blob.core.windows.net/umbraco-assets-corp/22127/pol186.pdfDate accessed: March 21, 2021Google Scholar is the only agency whose recently revised allocation algorithm considers 5(!) HLA loci for matching purposes, HLA-A, HLA-B, HLA-Cw, HLA-DR, and HLA-DQ, and removes 0, 100, 150, 250, and 500 points for 9 to 10, 4 to 8, 2 to 3, 1, and 0 mismatches, respectively. More details on other allocation systems worldwide are provided in Table 1.19Transplant Manitoba Gift of Life. Kidney allocation.https://www.transplantmanitoba.ca/transplant-program/kidney-allocationDate accessed: March 21, 2021Google ScholarTable 1Examples of HLA allocation schemesAllocation organizationAllocation systemHLA priority pointsPoints' equivalency for 1-year wait timeEurotransplantETKASConsider A-B-DR. The 0 mismatch = 400 points.Points are doubled for pediatric patients.33.3 PointsUNOSKASConsider only DR. The 0 mismatch = 2 points.Up to 4 points for pediatric patients aged 0–10 y.1.0 PointFrenchConsider A-B-DR-DQ. The 0 mismatch is the equivalent of 600 points.10 Points for the first year with algorithm to incorporate where patient is on dialysisNHSBTConsider A-B-C-DR-DQ. Point deduction system, with 0 mismatch being equivalent of 500 points.365 Points (1 point per day)New ZealandPoint elimination system. The 0 mismatch is the equivalent of 6000 points.12 PointsCanada19Transplant Manitoba Gift of Life. Kidney allocation.https://www.transplantmanitoba.ca/transplant-program/kidney-allocationDate accessed: March 21, 2021Google ScholarUp to 3 points for HLA-DRβ1/3/4/5 and HLA-DQβ1. Pediatric patients treated as high priority over adults, except for highly sensitized patients.1.0 PointETKAS, Eurotransplant Kidney Allocation System; HLA, human leukocyte antigen; KAS, kidney allocation system; NHSBT, British National Health System Blood and Transplant; UNOS, United Network of Organ Sharing. Open table in a new tab Consequences of de novo donor-specific HLA antibody developmentAn important consequence of donor-recipient HLA mismatching is the potential development of antibodies against the mismatched HLA antigens. The Humoral Theory, as put forth by Paul Terasaki,20Terasaki P.I. Humoral theory of transplantation.Am J Transplant. 2003; 3: 665-673Crossref PubMed Scopus (512) Google Scholar,21Terasaki P.I. A personal perspective: 100-year history of the humoral theory of transplantation.Transplantation. 2012; 93: 751-756Crossref PubMed Scopus (61) Google Scholar highlighted the role of humoral alloimmunity in graft outcome. The novelty of the humoral theory was in emphasizing the association between HLA donor-specific antibodies (DSAs) developing de novo, after transplantation, and decreased graft survival. In this context, it is important to appreciate that much of the evidence supporting a diminishing effect of HLA mismatching on transplant outcomes, which underpinned deemphasizing the role of HLA matching in the United States, was based on relatively short-term graft outcome data.22Nankivell B.J. Borrows R.J. Fung C.L. et al.The natural history of chronic allograft nephropathy.N Engl J Med. 2003; 349: 2326-2333Crossref PubMed Scopus (1645) Google Scholar,23Delmonico F.L. Milford E.L. Goguen J. et al.A novel United Network for Organ Sharing region kidney allocation plan improves transplant access for minority candidates.Transplantation. 1999; 68: 1875-1879Crossref PubMed Scopus (15) Google ScholarMultiple studies have shown the detrimental effect of de novo DSA development and antibody-mediated rejection (ABMR) on graft outcome.24Wiebe C. Gibson I.W. Blydt-Hansen T.D. et al.Evolution and clinical pathologic correlations of de novo donor-specific HLA antibody post kidney transplant.Am J Transplant. 2012; 12: 1157-1167Crossref PubMed Scopus (708) Google Scholar, 25Wiebe C. Gibson I.W. Blydt-Hansen T.D. et al.Rates and determinants of progression to graft failure in kidney allograft recipients with de novo donor-specific antibody.Am J Transplant. 2015; 15: 2921-2930Crossref PubMed Scopus (228) Google Scholar, 26Mehra N.K. Siddiqui J. Baranwal A. et al.Clinical relevance of antibody development in renal transplantation.Ann N Y Acad Sci. 2013; 1283: 30-42Crossref PubMed Scopus (22) Google Scholar More important, over half of the long-term kidney graft failure can be attributed to DSA-mediated long-term rejection.27Loupy A. Hill G.S. Jordan S.C. The impact of donor-specific anti-HLA antibodies on late kidney allograft failure.Nat Rev Nephrol. 2012; 8: 348-357Crossref PubMed Scopus (269) Google Scholar It has been shown that up to 30% of nonsensitized kidney transplant recipients develop de novo DSA within 10 years from transplantation and about 40% of patients lose their grafts within 5 years of development of de novo DSA.3Schrezenmeier E. Lehner L.J. Merkel M. et al.What happens after graft loss? a large, long-term, single-center observation.Transpl Int. 2021; 34: 732-742Crossref PubMed Scopus (3) Google Scholar,28Aubert O. Loupy A. Hidalgo L. et al.Antibody-mediated rejection due to preexisting versus de novo donor-specific antibodies in kidney allograft recipients.J Am Soc Nephrol. 2017; 28: 1912-1923Crossref PubMed Scopus (149) Google Scholar,29Lionaki S. Panagiotellis K. Iniotaki A. Boletis J.N. Incidence and clinical significance of de novo donor specific antibodies after kidney transplantation.Clin Dev Immunol. 2013; 2013: 849835Crossref PubMed Scopus (27) Google ScholarPatients developing de novo HLA-DSA and ABMR receive more potent immunosuppression regimens in an attempt to suppress antibody formation and thus mitigate graft injury to salvage kidney function. Beyond the financial implications associated with additional therapies30Muduma G. Odeyemi I. Smith-Palmer J. Pollock R.F. Review of the clinical and economic burden of antibody-mediated rejection in renal transplant recipients.Adv Ther. 2016; 33: 345-356Crossref PubMed Scopus (14) Google Scholar and their limited efficacy, immunosuppressive drugs come with a multitude of adverse effects (e.g., increased susceptibility to opportunistic infections, increased risk of malignancy, organ toxicity, and risk of hypertension and diabetes).31Susal C. Opelz G. Impact of HLA matching and HLA antibodies in organ transplantation: a collaborative transplant study view.Methods Mol Biol. 2012; 882: 267-277Crossref PubMed Scopus (15) Google Scholar,32Tonelli M. Wiebe N. Knoll G. et al.Systematic review: kidney transplantation compared with dialysis in clinically relevant outcomes.Am J Transplant. 2011; 11: 2093-2109Crossref PubMed Scopus (712) Google Scholar As mentioned above, ABMR is a leading cause of graft failure, often time necessitating return of the patient to dialysis.33Bonani M. Achermann R. Seeger H. et al.Dialysis after graft loss: a Swiss experience.Nephrol Dial Transplant. 2020; 35: 2182-2190Crossref PubMed Google Scholar,34Brar A. Markell M. Stefanov D.G. et al.Mortality after renal allograft failure and return to dialysis.Am J Nephrol. 2017; 45: 180-186Crossref PubMed Scopus (26) Google Scholar The impact of DSA development on patient quality of life is therefore significant.Among those patients fortunate to be medically suitable for retransplantation, many will show increased levels of sensitization (presence of preformed HLA antibodies), as can be calculated by a variety of approaches looking at panel-reactive antibody (calculation panel-reactive antibody [cPRA]/virtual panel-reactive antibody/calculated reaction frequency [the percentage of a standardized panel of 10,000 consecutive HLA-typed UK deceased organ donors who is blood group identical but HLA incompatible with the alloantibody profile of a potential transplant recipient]).3Schrezenmeier E. Lehner L.J. Merkel M. et al.What happens after graft loss? a large, long-term, single-center observation.Transpl Int. 2021; 34: 732-742Crossref PubMed Scopus (3) Google Scholar It is important to appreciate that, because of the high degree of homology between different HLA antigens, development of HLA-DSA often means generation of antibodies that recognize not only those antigens expressed by the organ donor, but also recognize multiple other HLA antigens. For example, antibodies developed against donor HLA-B57 antigen have a high likelihood of also recognizing A2, A23, A24, A68, A69, and B58 (that are part of the same cross reactive group as B57). In this example, although B57 is present in 7% of the population, according to the UNOS cPRA calculator, the proportion of potential donors who may be recognized by this antibody can be as high as 75%. It follows that patients who lost their graft and developed HLA antibodies are likely to have broader humoral alloreactivity than the mere frequency of their mismatched donor antigens that had driven DSA formation (Figure 1). A single-center study35Kosmoliaptsis V. Gjorgjimajkoska O. Sharples L.D. et al.Impact of donor mismatches at individual HLA-A, -B, -C, -DR, and -DQ loci on the development of HLA-specific antibodies in patients listed for repeat renal transplantation.Kidney Int. 2014; 86: 1039-1048Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar demonstrated that the risk of sensitization after failure of a first kidney transplant increases incrementally with the number of HLA mismatches in HLA-A, HLA-B, HLA-DR, and HLA-DQ loci. This can have a profound impact on the likelihood of finding a second, antibody-compatible, kidney donor.3Schrezenmeier E. Lehner L.J. Merkel M. et al.What happens after graft loss? a large, long-term, single-center observation.Transpl Int. 2021; 34: 732-742Crossref PubMed Scopus (3) Google ScholarAccording to OPTN data, approximately 12% of the waitlist patients in 2020 were awaiting retransplantation, with 9.8% of these patients receiving a deceased donor transplant. Similar frequencies were observed in Eurotransplant, with 17% retransplant candidates on the waitlist and 13% proceeding to transplantation; and in the United Kingdom, with 22% of candidates awaiting retransplantation and 16% receiving retransplantation. The impact of sensitization in patients awaiting primary kidney transplantation versus retransplantation is shown in Figure 2a (OPTN data) and Supplementary Figure S1 (UK data).Figure 2(a) Comparison between patients awaiting primary kidney transplant and those awaiting repeat transplantation, as observed in the United States; data obtained from the Organ Procurement and Transplant Network (OPTN) in April 2021. Although about 64% of patients awaiting first transplant have 0% calculation panel-reactive antibody (cPRA), this proportion decreases down to only 27% among patients awaiting retransplant. Conversely, 2% and 4% of the patients awaiting first transplant have a cPRA of 98% to 100% or 80% to 97%, respectively, whereas this proportion grows to 31% of patients awaiting retransplant and exhibiting a cPRA of 98% to 100%; an additional 18% have a cPRA of 80% to 97%, for a total of almost half the patients awaiting repeat transplantation. (b) The peril of sensitization following the first transplant: comparing pediatric with adult patients. Data were obtained from the US OPTN in April 2021. Pediatric patients, who are often in need of second or third transplants, are more prone to develop high levels of sensitization following their first transplantation. Although the overall number of pediatric patients awaiting retransplant is not high, about 39% of these patients exhibit cPRAs of ≥98%.View Large Image Figure ViewerDownload Hi-res image Download (PPT)It is important to emphasize that the perils of sensitization following the first transplant are worse in the pediatric and young-adult population as these patients are more likely to require >1 additional transplant in their lifetime. Consequently, young patients are disproportionally affected by reduced access to the donor pool and are subjected to increased waiting time (Figure 2b). For example, it was shown in the United States that 20% to 40% of children with a failed first transplant would be awaiting retransplantation for >10 years, depending on the level of HLA mismatch with the first donor.36Foster B.J. Dahhou M. Zhang X. et al.Impact of HLA mismatch at first kidney transplant on lifetime with graft function in young recipients.Am J Transplant. 2014; 14: 876-885Crossref PubMed Scopus (35) Google ScholarAt the societal level, the overall financial burden to the taxpayer is significant as dialysis programs are one of the largest costs for the Centers for Medicare & Medicaid Services, with ~$50 billion per year (US Renal Data System 2020 Annual Report: epidemiology of kidney disease in the United States). Finally, graft loss and returning to the waiting list means more patients "competing" on the limited resource of deceased donor organs. Taken together, it becomes apparent that the detrimental effect of donor-recipient HLA mismatching is multifaceted, as shown in Figure 3, underpinning the need for further research and development of effective public policy in this area.Figure 3The vicious cycle of human leukocyte antigen (HLA) mismatched transplantation and antibody-mediated rejection (ABMR). Ignoring HLA mismatching may expedite receiving the first kidney transplantation, but also puts patients at an increased risk of developing de novo donor-specific antibody (DSA), episodes of ABMR, adverse effects from intensified immunosuppression, graft failure, return to dialysis, and prolonged wait time as sensitized patients. Consequences on both the patient and society are listed. cPRA, calculation panel-reactive antibody.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Impact of HLA-DQ DSA on graft and patient outcomesAlthough all de novo HLA-DSAs have a detrimental effect on solid organ transplant outcome, we now appreciate that the vast majority of de novo antibodies target specifically donor HLA-DQ molecules.24Wiebe C. Gibson I.W. Blydt-Hansen T.D. et al.Evolution and clinical pathologic correlations of de novo donor-specific HLA antibody post kidney transplant.Am J Transplant. 2012; 12: 1157-1167Crossref PubMed Scopus (708) Google Scholar A breakthrough providing the evidence for this effect came about with the introduction of the single-antigen bead assay to routine testing algorithms. Iniotaki-Theodoraki et al.37Iniotaki-Theodoraki A.G. Boletis J.N. Trigas G. et al.Humoral immune reactivity against human leukocyte antigen (HLA)-DQ graft molecules in the early posttransplantation period.Transplantation. 2003; 75: 1601-1603Crossref PubMed Scopus (27) Google Scholar were among the first to report high incidence of HLA-DQ DSA early post-transplant in recipients of kidney allografts. Ozawa et al.38Ozawa M. Rebellato L.M. Terasaki P.I. et al.Longitudinal testing of 266 renal allograft patients for HLA and MICA antibodies: Greenville experience.Clin Transpl. 2006; : 265-290PubMed Google Scholar showed that most patients with failed grafts developed de novo DSA before graft loss and most of these antibodies were directed against HLA-DQ. DeVos et al.39DeVos J.M. Gaber A.O. Knight R.J. et al.Donor-specific HLA-DQ antibodies may contribute to poor graft outcome after renal transplantation.Kidney Int. 2012; 82: 598-604Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar prospectively monitored renal transplant recipients and showed that 77% of patients with de novo DSA targeted donor HLA-DQ and exhibited inferior graft outcome. Willicombe et al.40Willicombe M. Brookes P. Sergeant R. et al.De novo DQ donor-specific antibodies are associated with a significant risk of antibody-mediated rejection and transplant glomerulopathy.Transplantation. 2012; 94: 172-177Crossref PubMed Scopus (175) Google Scholar reported that 54% of patients with de novo DSA had antibodies to donor HLA-DQ and had significant risk for ABMR, transplant glomerulopathy, and graft loss. Similar findings, demonstrating high incidence of de novo HLA-DQ DSA among recipients of kidney or other solid organs, as well as their effect on allograft rejection and graft loss, have been reported.41Everly M.J. Rebellato L.M. Haisch C.E. et al.Incidence and impact of de novo donor-specific alloantibody in primary renal allografts.Transplantation. 2013; 95: 410-417Crossref PubMed Scopus (284) Google Scholar, 42Freitas M.C. Rebellato L.M. Ozawa M. et al.The role of immunoglobulin-G subclasses and C1q in de novo HLA-DQ donor-specific antibody kidney transplantation outcomes.Transplantation. 2013; 95: 1113-1119Crossref PubMed Scopus (138) Google Scholar, 43Ticehurst E.H. Molina M.R. Frank R. et al.Antibody-mediated rejection in heart transplant patients: long-term follow up of patients with high levels of donor-directed anti-DQ antibodies.Clin Transpl. 2011; : 409-414PubMed Google Scholar, 44Irving C.A. Carter V. Gennery A.R. et al.Effect of persistent versus transient donor-specific HLA antibodies on graft outcomes in pediatric cardiac transplantation.J Heart Lung Transplant. 2015; 34: 1310-1317Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar, 45Lobo L.J. Aris R.M. Schmitz J. Neuringer I.P. Donor-specific antibodies are associated with antibody-mediated rejection, acute cellular rejection, bronchiolitis obliterans syndrome, and cys