The association between human leukocyte antigen eplet mismatches, de novo donor-specific antibodies, and the risk of acute rejection in pediatric kidney transplant recipients

Sharma, Ankit; Taverniti, A.; Graf, Nicole; Teixeira‐Pinto, Armando; Lewis, Joshua R.; Lim, Wai H.; Alexander, Stephen I.; Durkan, Anne; Craig, Jonathan C.; Wong, Germaine

doi:10.1007/s00467-020-04474-x

Cited by 17 publications

(22 citation statements)

References 19 publications

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“…Interestingly, HLA Class II mismatch status did not significantly influence dnDSA incidence in our study. Although HLA mismatching is a significant risk factor of dnDSA development, non‐adherence remains the primary origin of dnDSA emergence, while newly recognized clinical factors, such as intra‐patient tacrolimus variability, may also contribute to dnDSA incidence 7,8,18,19 7,20,21 …”

Section: Discussionmentioning

confidence: 99%

“…Moreover, HLA eplet incompatibility, which has been suggested as an improvement to HLA antigen mismatch determination, could identify acceptable mismatches among antigens that may appear to be foreign for the host immune system 7,20,21 7,20,21 …”

Section: Discussionmentioning

confidence: 99%

“…In clinical pediatric KTx studies, the presence of de novo DSA (dnDSA) has been widely associated with a higher risk of acute humoral and cellular rejection 6–8 …”

Section: Introductionmentioning

confidence: 99%

“…4,5 In clinical pediatric KTx studies, the presence of de novo DSA (dnDSA) has been widely associated with a higher risk of acute humoral and cellular rejection. [6][7][8] Nevertheless, the clinical impact of dnDSA on long-term allograft prognosis has not been clarified yet.…”

Section: Introductionmentioning

confidence: 99%

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Impact of de novo donor‐specific HLA antibodies on pediatric kidney transplant prognosis in patients with acute declined or stable allograft function

Fylaktou

Karava

Vittoraki

et al. 2022

Pediatric Transplantation

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Background This retrospective multicenter long‐term cohort study investigates de novo donor‐specific HLA antibodies (dnDSA) impact on allograft survival in pediatric kidney transplantation (KTx), depending on allograft function at dnDSA detection. Methods Seventy patients with dnDSA screening in the context of acute allograft dysfunction (AAD) (>50% serum creatinine increase) or routine follow‐up were included during a 20‐year period. Number of dnDSA specificities and HLA total mean fluorescence intensity (MFI‐sum) were collected. Results Median follow‐up time was 8.6 years. Among the 22 dnDSA+ patients, 8 patients presented AAD. Compared with dnDSA− patients, allograft survival was shorter only in dnDSA+/AAD+ patients, regardless of dnDSA detection during the 5‐year post‐transplant period (9 patients) or later (13 patients) (log rank p < .001 and p < .001, respectively). One dnDSA+/AAD−, 7 dnDSA+/AAD+, and 5 dnDSA− patients lost their allograft. Allograft survival was shorter in dnDSA+/AAD+ patients compared with the 16 dnDSA−/AAD+ patients (log rank p < .001) but did not differ between dnDSA+/AAD− and dnDSA−/AAD− patients (log rank p = .157). dnDSA+/AAD+ and dnDSA−/AAD+ patients presented higher risk of allograft failure compared with the other patient groups after adjustment for recipient age at KTx, donor type, and incidence of delayed graft function (HR 11.322, 95% CI 3.094–41.429, p < .001). Concurrent MFI‐sum >10 000 and multiple dnDSA specificities were more significantly associated with AAD, compared with each factor separately (p < .001). Conclusions In pediatric KTx, AAD shortens allograft survival in dnDSA+ patients, regardless of dnDSA time detection, and is commonly observed when high MFI‐sum concurs with multiple dnDSA specificities. dnDSA without AAD incidence does not determinately affect allograft survival.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…In clinical pediatric KTx studies, the presence of de novo DSA (dnDSA) has been widely associated with a higher risk of acute humoral and cellular rejection 6–8 …”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Impact of de novo donor‐specific HLA antibodies on pediatric kidney transplant prognosis in patients with acute declined or stable allograft function

Fylaktou

Karava

Vittoraki

et al. 2022

Pediatric Transplantation

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“…While many studies focus on kidney transplantation, the link between eplet (in)compatibility and patient outcomes remains consistent in the context of other solid organ transplants (Hamada et al., 2020; McCaughan et al., 2018; Walton et al., 2016). Importantly, a better understanding of immune risk associated with eplet incompatibility can inform surveillance schedules and personalized immunosuppression regimens in both adult and paediatric patients (Sharma et al., 2020; Wiebe et al., 2015; Wiebe & Nickerson, 2020; Wiebe et al., 2017).…”

Section: Assessing Incompatibility At the Level Of Hla Epletsmentioning

confidence: 99%

Matchmaker, matchmaker make me a match: Opportunities and challenges in optimizing compatibility of HLA eplets in transplantation

Lemieux

Mohammadhassanzadeh

Klement

et al. 2021

Int J Immunogenetics

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The development of donor‐specific antibodies (DSAs) is a major complication in transplantation, which is associated with inferior graft survival, impaired quality of life, and increased healthcare costs. DSA develop upon recognition of nonself HLA by the recipient's immune system. HLA molecules contain epitopes, which are the surface regions of HLA molecules recognized by antibodies. HLAMatchmaker is an algorithm for assessing donor:recipient HLA compatibility at the level of structurally defined HLA targets called eplets. The consideration of eplets, rather than the whole HLA molecule, could offer some advantages when classifying the immune risk associated with particular donor:recipient pairs. Assessing compatibility at the level of HLA eplets could decrease misclassification of post‐transplant immune risk by improving specificity, when antibodies are confirmed to be directed against donor eplets missing from the recipient's repertoire of eplets. Consideration of eplets may also increase the sensitivity of immune risk assessment, when identifying mismatched eplets that could give rise to new, not previously detected, donor‐specific antibodies post‐transplant. Eplet matching can serve as a rational strategy for immune risk mitigation. Herein, we review the evolution of HLA (in) compatibility assessment for organ allocation. We outline challenges in the implementation of eplet‐based donor:recipient matching, including unavailability of allele‐level donor genotypes for 11 HLA loci at the time of organ allocation and difficulty in assessing the hierarchy of immune risk associated with particular HLA eplet mismatches. Opportunities to address some of the current shortcomings of donor genotyping and HLAMatchmaker are also discussed. While there is a demonstrated benefit in the application of HLAMatchmaker for donor: recipient HLA (in)compatibility assessment, evolving long‐read genotyping methods, compilation of large data sets with allele‐level genotypes, and standardization of methods to verify eplets as determinants of immune‐mediated injuries are required before HLA eplet matching is implemented in organ allocation to improve upon transplant outcomes.

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Renal Transplantation: Evaluation of Children and Donors

Strologo

Grenda

2022

Pediatric Nephrology

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The association between human leukocyte antigen eplet mismatches, de novo donor-specific antibodies, and the risk of acute rejection in pediatric kidney transplant recipients

Cited by 17 publications

References 19 publications

Impact of de novo donor‐specific HLA antibodies on pediatric kidney transplant prognosis in patients with acute declined or stable allograft function

Impact of de novo donor‐specific HLA antibodies on pediatric kidney transplant prognosis in patients with acute declined or stable allograft function

Matchmaker, matchmaker make me a match: Opportunities and challenges in optimizing compatibility of HLA eplets in transplantation

Renal Transplantation: Evaluation of Children and Donors

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