De Novo DQ Donor-Specific Antibodies Are Associated With a Significant Risk of Antibody-Mediated Rejection and Transplant Glomerulopathy

Willicombe, Michelle; Brookes, Paul; Sergeant, Ruhena; Santos‐Nunez, Eva; Steggar, Corinna; Galliford, Jack; McLean, A.G.; Cook, Terence; Cairns, Tom; Roufosse, Candice; Taube, David

doi:10.1097/tp.0b013e3182543950

Cited by 222 publications

(230 citation statements)

References 5 publications

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“…Studies involving pediatric and adult kidney transplant only and kidney-pancreas transplant recipients have also shown that the development of de novo donor-specific anti-HLA-DQ antibody was associated with a #10-fold greater risk of developing early and late AMR, which was often associated with development of transplant glomerulopathy and early graft loss (14)(15)(16). In our study, we have highlighted the importance of class 2 mismatches and the risk of acute rejection.…”

Section: Discussionmentioning

confidence: 69%

HLA-DQ Mismatches and Rejection in Kidney Transplant Recipients

Lim

Chapman

Coates

et al. 2016

CJASN

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Background and objectives The current allocation algorithm for deceased donor kidney transplantation takes into consideration HLA mismatches at the ABDR loci but not HLA mismatches at other loci, including HLA-DQ. However, the independent effects of incompatibilities for the closely linked HLA-DQ antigens in the context of HLA-DR antigen matched and mismatched allografts are uncertain. We aimed to determine the effect of HLA-DQ mismatches on renal allograft outcomes.Design, setting, participants, & measurements Using data from the Australia and New Zealand Dialysis and Transplant Registry, we examined the association between HLA-DQ mismatches and acute rejections in primary live and deceased donor kidney transplant recipients between 2004 and 2012 using adjusted Cox regression models.Results Of the 788 recipients followed for a median of 2.8 years (resulting in 2891 person-years), 321 (40.7%) and 467 (59.3%) received zero and one or two HLA-DQ mismatched kidneys, respectively. Compared with recipients who have received zero HLA-DQ mismatched kidneys, those who have received one or two HLA-DQ mismatched kidneys experienced greater numbers of any rejection (50 of 321 versus 117 of 467; P,0.01), late rejections (occurring .6 months post-transplant; 8 of 321 versus 27 of 467; P=0.03), and antibody-mediated rejections (AMRs; 12 of 321 versus 38 of 467; P=0.01). Compared with recipients of zero HLA-DQ mismatched kidneys, the adjusted hazard ratios for any and late rejections in recipients who had received one or two HLA-DQ mismatched kidneys were 1.54 (95% confidence interval [95% CI], 1.08 to 2.19) and 2.85 (95% CI, 1.05 to 7.75), respectively. HLA-DR was an effect modifier between HLA-DQ mismatches and AMR (P value for interaction =0.02), such that the association between HLA-DQ mismatches and AMR was statistically significant in those who have received one or two HLA-DR mismatched kidneys, with adjusted hazard ratio of 2.50 (95% CI, 1.05 to 5.94).Conclusions HLA-DQ mismatches are associated with acute rejection, independent of HLA-ABDR mismatches and initial immunosuppression. Clinicians should be aware of the potential importance of HLA-DQ matching in the assessment of immunologic risk in kidney transplant recipients.

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Section: Discussionmentioning

confidence: 69%

HLA-DQ Mismatches and Rejection in Kidney Transplant Recipients

Lim

Chapman

Coates

et al. 2016

CJASN

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“…This observation does not necessarily challenge (25,66) the role of HLA-DQ eplet mismatches in the development of TG; but rather sheds lights on the potential diversity of eplet immunogenicity and the unique interactions of HLA-DQB/-DQA chains (in contrast to the single polymorphic HLA-DRB1 chain) with antibodies. While a greater eplet load may indicate a greater risk for experiencing antibody-mediated injuries from de novo DSA, it is the presence (or absence) of highly immunogenic eplet mismatches that help refine this risk.…”

Section: Discussionmentioning

confidence: 99%

“…There has been a growing recognition that HLA antibodies are directed toward structurally defined HLA epitopes (60) rather than HLA antigens (21,25,26). Duquesnoy et al (37), for example, showed that patients with DRB1/3/4/5 antibodies were exposed to twice as many mismatched eplets as those who did not show antibodies (21.4 AE 8.0 vs. 10.6 AE 7.8, p < 0.0001).…”

Section: Discussionmentioning

confidence: 99%

“…Absence of a dose-response relationship between HLA-DQ eplet load and TG is curious considering the dominance of anti-HLA-DQ antibodies among HLA class II de novo DSA (25,56,(63)(64)(65). This observation does not necessarily challenge (25,66) the role of HLA-DQ eplet mismatches in the development of TG; but rather sheds lights on the potential diversity of eplet immunogenicity and the unique interactions of HLA-DQB/-DQA chains (in contrast to the single polymorphic HLA-DRB1 chain) with antibodies.…”

Section: Discussionmentioning

confidence: 99%

“…TG develops as a consequence of overt and covert episodes of antibody-mediated rejection (5,(18)(19)(20)(21)(22)(23)(24), typically, due to HLA class II anti-HLA antibodies (5,10,(25)(26)(27)(28)(29)(30). Antibodies against HLA develop when antibody-accessible polymorphic residues on HLA antigens are recognized as ''nonself.''…”

Section: Introductionmentioning

confidence: 99%

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HLA-DR and -DQ Eplet Mismatches and Transplant Glomerulopathy: A Nested Case–Control Study

Sapir‐Pichhadze

Tinckam

Quach

et al. 2015

American Journal of Transplantation

116

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We conducted a nested case-control study from a cohort of adult kidney transplant recipients to assess the risk of transplant glomerulopathy (TG) as a function of donor and recipient HLA-DR and -DQ incompatibility at the eplet level. Cases (n ¼ 52) were defined as patients diagnosed with transplant glomerulopathy based on biopsies showing glomerular basement membrane duplication without immune complex deposition. Controls (n ¼ 104) with a similar follow-up from transplantation were randomly selected from the remaining cohort. HLAMatchmaker was used to ascertain the number of DRB1/3/4/5, DQA1 and DQB1 related eplet mismatches (eplet load). Multivariable conditional logistic regression models demonstrated an increase in the odds of TG (odds ratios [OR] of 2.84 [95% confidence interval (CI): 1.03, 7.84] and 4.62 [95% CI: 1.51, 14.14]) in the presence of 27-43 and >43 HLA-DR þ DQ related eplet mismatches versus <27 eplet mismatches, respectively. When the eplet load was modeled as a continuous variable, the OR for TG was 1.25 (95% CI: 1.04, 1.50) for every 10 additional HLA-DR þ DQ eplet mismatches. Our study suggests that minimization of HLA-DR þ DQ eplet mismatches may decrease the incidence of transplant glomerulopathy diagnosed by indication biopsies. The role of eplet immunogenicity/antigenicity as determinants of allograft outcomes requires further study.

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De NovoDonor-Specific HLA Antibodies Decrease Patient and Graft Survival in Liver Transplant Recipients

Kaneku

O’Leary

Banuelos

et al. 2013

American Journal of Transplantation

102

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The role of de novo donor-specific HLA antibodies (DSA) in liver transplantation remains unknown as most of the previous studies have only focused on preformed HLA antibodies. To understand the significance of de novo DSA, we designed a retrospective cohort study of 749 adult liver transplant recipients with pre- and posttransplant serum samples that were analyzed for DSA. We found that 8.1% of patients developed de novo DSA 1 year after transplant; almost all de novo DSAs were against HLA class II antigens, and the majority were against DQ antigens. In multivariable modeling, the use of cyclosporine (as opposed to tacrolimus) and low calcineurin inhibitor levels increased the risk of de novo DSA formation, while a calculated MELD score >15 at transplant and recipient age >60 years old reduced the risk. Multivariable analysis also demonstrated that patients with de novo DSA at 1-year had significantly lower patient and graft survival. In conclusion, we demonstrate that de novo DSA development after liver transplantation is an independent risk factor for patient death and graft loss.

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De Novo DQ Donor-Specific Antibodies Are Associated With a Significant Risk of Antibody-Mediated Rejection and Transplant Glomerulopathy

Abstract: DQ DSAbs are associated with inferior allograft outcomes. This study shows the importance of establishing the DQ match before transplantation to define immunologic risk.

Cited by 222 publications

References 5 publications

HLA-DQ Mismatches and Rejection in Kidney Transplant Recipients

HLA-DQ Mismatches and Rejection in Kidney Transplant Recipients

HLA-DR and -DQ Eplet Mismatches and Transplant Glomerulopathy: A Nested Case–Control Study

De NovoDonor-Specific HLA Antibodies Decrease Patient and Graft Survival in Liver Transplant Recipients

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