Elevated AT1R Antibody and Morbidity in Patients Bridged to Heart Transplant Using Continuous Flow Left Ventricular Assist Devices

Chau, Vinh Q.; Flattery, Maureen; Nicholson, Kate; McDougan, Felecia; Gupta, Gaurav; Uber, Patricia A.; Priday, Anna; Desai, K.; Kimball, Pamela; Shah, Keyur B.

doi:10.1016/j.cardfail.2020.06.010

Cited by 11 publications

(8 citation statements)

References 27 publications

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“…Next, an extension of anti-AT1R mediated injury to nonkidney organs and a more generalized role for this autoantigen in allo-transplantation is also identifiable (87,88). However, aside from autoimmunity, in our work, we identified that increased genome-wide mismatch was proportional to AT1Rlocus mismatches.…”

Section: At1rmentioning

confidence: 49%

Donor–Recipient Non-HLA Variants, Mismatches and Renal Allograft Outcomes: Evolving Paradigms

et al. 2022

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Despite significant improvement in the rates of acute allograft rejection, proportionate improvements in kidney allograft longevity have not been realized, and are a source of intense research efforts. Emerging translational data and natural history studies suggest a role for anti-donor immune mechanisms in a majority of cases of allograft loss without patient death, even when overt evidence of acute rejection is not identified. At the level of the donor and recipient genome, differences in highly polymorphic HLA genes are routinely evaluated between donor and recipient pairs as part of organ allocation process, and utilized for patient-tailored induction and maintenance immunosuppression. However, a growing body of data have characterized specific variants in donor and recipient genes, outside of HLA loci, that induce phenotypic changes in donor organs or the recipient immune system, impacting transplant outcomes. Newer mechanisms for “mismatches” in these non-HLA loci have also been proposed during donor–recipient genome interactions with transplantation. Here, we review important recent data evaluating the role of non-HLA genetic loci and genome-wide donor-recipient mismatches in kidney allograft outcomes.

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Section: At1rmentioning

confidence: 49%

Donor–Recipient Non-HLA Variants, Mismatches and Renal Allograft Outcomes: Evolving Paradigms

et al. 2022

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“…Although it has been difficult to correlate AT1R-Ab preleft ventricular assist device or pre-OHT with survival, 15 there is evidence that increasing AT1R-Ab level at the time of OHT is associated with posttransplant morbidity. 24 It is thus possible that earlier testing in our high-titer cohort would have revealed elevated titers early, and mitigation measures may have been more impactful. Consistent with our experience, these studies suggest the assessment of both DSA and AT1R-Ab together to determine a comprehensive immunologic risk.…”

Section: Discussionmentioning

confidence: 99%

Angiotensin II Type 1 Receptor Antibody-mediated Rejection Following Orthotopic Heart Transplant: A Single-center Experience

et al. 2022

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Background. Antibody-mediated rejection (AMR) following orthotopic heart transplant (OHT) causes significant morbidity and mortality. There are limited data on antibodies to the angiotensin II type 1 receptor antibody (AT1R-Ab) causing rejection following OHT. Methods. This is a retrospective, single-center study that presents our 2-y experience with a series of 11 patients with evidence of nonspecific graft dysfunction and pathologic levels of AT1R-Ab. The clinical outcomes and treatments were compared to a group of 10 patients, also with evidence of nonspecific graft dysfunction, but who had nonsignificant AT1R-Ab titers. Results. The mean age of the AT1R-Ab cohort was 52% and 73% were bridged to transplant with an left ventricular assist device. The average left ventricular ejection fraction at presentation was 45%, and most were not on an angiotensin receptor blocker (ARB). Endomyocardial biopsies in those with elevated AT1R-Ab levels frequently showed reactive endothelium/endocardium without C4d or intravascular CD68 staining. Ten patients (91%) were started on an ARB. Other therapies included plasmapheresis and IVIg (64%), with 4 patients also receiving rituximab. Most patients had symptom improvement, but minimal change in graft function at an average 6 mo of follow-up. Conclusions. The role of AT1R-Ab-mediated rejection in OHT recipients remains poorly understood. More than half of patients at our center who presented with graft dysfunction in the absence of acute cellular rejection or AMR were found to have elevated AT1R-Ab titers. Empiric AMR treatment in conjunction with ARB therapy may improve patient outcomes. Future studies are needed to better define the optimal treatment modalities for ATR1-Ab-mediated AMR.

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“…73 An evaluation of 77 patients bridged to HT with ventricular assist devices showed that elevated AT1R (angiotensin II type 1 receptor) antibodies (and not HLA-Abs) at time of transplant were associated with an increased composite risk of death, treated rejection, or CAV within a 5-year follow-up period. 74 There have also been reported associations between CAR and antibodies to collagen V, K-alpha-1 tubulin, and MICA (major histocompatibility complex class I chain-related molecule A). 75,76 Given the numerous potential non-HLA antibodies related to CAR, future evaluations in this area will benefit from ongoing work describing the use of protein expression profiling as well as the development of a Luminex bead assay for non-HLA antigens.…”

Section: Non-hla Antibodiesmentioning

confidence: 99%

Selection and Interpretation of Molecular Diagnostics in Heart Transplantation

Goldberg,

Truby,

Agbor-Enoh

et al. 2023

Circulation

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The number of heart transplants performed annually in the United States and worldwide continues to increase, but there has been little change in graft longevity and patient survival over the past 2 decades. The reference standard for diagnosis of acute cellular and antibody-mediated rejection includes histologic and immunofluorescence evaluation of endomyocardial biopsy samples, despite invasiveness and high interrater variability for grading histologic rejection. Circulating biomarkers and molecular diagnostics have shown substantial predictive value in rejection monitoring, and emerging data support their use in diagnosing other posttransplant complications. The use of genomic (cell-free DNA), transcriptomic (mRNA and microRNA profiling), and proteomic (protein expression quantitation) methodologies in diagnosis of these posttransplant outcomes has been evaluated with varying levels of evidence. In parallel, growing knowledge about the genetically mediated immune response leading to rejection (immunogenetics) has enhanced understanding of antibody-mediated rejection, associated graft dysfunction, and death. Antibodies to donor human leukocyte antigens and the technology available to evaluate these antibodies continues to evolve. This review aims to provide an overview of biomarker and immunologic tests used to diagnose posttransplant complications. This includes a discussion of pediatric heart transplantation and the disparate rates of rejection and death experienced by Black patients receiving a heart transplant. This review describes diagnostic modalities that are available and used after transplant and the landscape of future investigations needed to enhance patient outcomes after heart transplantation.

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Elevated AT1R Antibody and Morbidity in Patients Bridged to Heart Transplant Using Continuous Flow Left Ventricular Assist Devices

Cited by 11 publications

References 27 publications

Donor–Recipient Non-HLA Variants, Mismatches and Renal Allograft Outcomes: Evolving Paradigms

Donor–Recipient Non-HLA Variants, Mismatches and Renal Allograft Outcomes: Evolving Paradigms

Angiotensin II Type 1 Receptor Antibody-mediated Rejection Following Orthotopic Heart Transplant: A Single-center Experience

Selection and Interpretation of Molecular Diagnostics in Heart Transplantation

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