Introduction
Antibody mediated rejection (ABMR) is a major factor limiting outcome after organ transplantation. Anti-HLA donor-specific antibodies (DSA) of the IgG isotype are mainly responsible for ...ABMR. Recently DSA of the IgE isotype were demonstrated in murine models as well as in a small cohort of sensitized transplant recipients. In the present study, we aimed to determine the frequency of pre-existing and
de novo
anti-HLA IgE antibodies in a cohort of 105 solid organ transplant recipients.
Methods
We prospectively measured anti-HLA IgE antibodies in a cohort of kidney (n=60), liver, heart and lung (n=15 each) transplant recipients before and within one-year after transplantation, employing a single-antigen bead assay for HLA class I and class II antigens. Functional activity of anti-HLA IgE antibodies was assessed by an
in vitro
mediator release assay. Antibodies of the IgG1-4 subclasses and Th1 and Th2 cytokines were measured in anti-HLA IgE positive patients.
Results
Pre-existing anti-HLA IgE antibodies were detected in 10% of renal recipients (including 3.3% IgE-DSA) and in 4.4% of non-renal solid organ transplant recipients (heart, liver and lung cohort). Anti-HLA IgE occurred only in patients that were positive for anti-HLA IgG, and most IgE positive patients had had a previous transplant. Only a small fraction of patients developed
de novo
anti-HLA IgE antibodies (1.7% of kidney recipients and 4.4% of non-renal recipients), whereas no
de novo
IgE-DSA was detected. IgG subclass antibodies showed a distinct pattern in patients who were positive for anti-HLA IgE. Moreover, patients with anti-HLA IgE showed elevated Th2 and also Th1 cytokine levels. Serum from IgE positive recipients led to degranulation of basophils
in vitro
, demonstrating functionality of anti-HLA IgE.
Discussion
These data demonstrate that anti-HLA IgE antibodies occur at low frequency in kidney, liver, heart and lung transplant recipients. Anti-HLA IgE development is associated with sensitization at the IgG level, in particular through previous transplants and distinct IgG subclasses. Taken together, HLA specific IgE sensitization is a new phenomenon in solid organ transplant recipients whose potential relevance for allograft injury requires further investigation.
Background
Sympathetic reinnervation after heart transplantation (HTX) is a known phenomenon, which has an impact on patient heart rate variability and exercise capacity. The impact of reinnervation ...on myocardial structure has not been evaluated yet.
Propose
To evaluate the feasibility of simultaneous imaging of cardiac reinnervation and cardiac structure using a hybrid PET/MRI system.
Study type
Prospective / pilot study.
Subjects
Ten patients, 4–21 years after cardiac transplantation.
Field Strength/Sequence
3 T hybrid PET/MRI system. Cine SSFP, T1 mapping (modified Look–Locker inversion recovery sequence) pre/postcontrast as well as dynamic 11Cmeta‐hydroxyephedrine (11CmHED) PET.
Assessment
All MRI and PET parameters were evaluated by experienced readers using dedicated postprocessing software packages for cardiac MRI and PET. For all parameters a 16‐segment model for the left ventricle was applied.
Statistical Tests
Mann–Whitney U‐test; Spearman correlations.
Results
Thirty‐six of 160 myocardial segments showed evidence of reinnervation by PET. On a segment‐based analysis, mean native T1 relaxation times were nonsignificantly altered in segments with evidence of reinnervation (1305 ± 151 msec vs. 1270 ± 112 msec; P = 0.1), whereas mean extracellular volume (ECV) was significantly higher in segments with evidence of reinnervation (35.8 ± 11% vs. 30.9 ± 7%; P = 0.019). There were no significant differences in wall motion (WM) and wall thickening (WT) between segments with or without reinnervation (mean WM: 7.6 ± 4 mm vs. group B: 9.3 ± 7 mm P = 0.13; WT: 79 ± 63% vs. 94 ± 74% P = 0.27) under resting conditions.
Data Conclusion
The assessment of cardiac reinnervation using a hybrid PET/MRI system is feasible. Segments with evidence of reinnervation by PET showed nonsignificantly higher T1 relaxation times and a significantly higher ECV, suggesting a higher percentage of diffuse fibrosis in these segments, without impairment of rest WM and WT.
Level of Evidence: 3
Technical Efficacy: Stage 3
J. Magn. Reson. Imaging 2019;50:1326–1335.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Abstract The mode of action of rabbit antithymocyte globulin (rATG) includes preferential inhibition of pre-existing donor-reactive memory T-cell reconstitution and possibly apoptosis of plasma ...cells, the source of donor specific antibodies (DSAs). In kidney transplant patients with low-strength preformed DSAs, non-comparative data have shown a low incidence of antibody-mediated rejection (ABMR) and graft survival using rATG even without desensitization procedures. For high strengths of preformed DSAs, rATG induction with more aggressive desensitization appears effective, with mixed results concerning the addition of B-cell specific agents. Regarding production of de novo DSA (dnDSA), interpretation of retrospective analyses is limited by selective use of rATG in higher-risk patients. Observational data in moderately sensitized kidney transplant patients suggest that the incidence of dnDSA and ABMR is significantly lower with rATG versus basiliximab. A randomized pilot study has suggested that addition of rituximab or bortezomib may not further inhibit dnDSA production in rATG-treated patients. Overall, rATG appears to inhibit DSA production, with a potential role in reducing the risk of ABMR in kidney transplant patients with high-strength preformed DSA, or lowering dnDSA in moderately sensitized patients. Randomized trials are awaited.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The aim of this study was to design and validate a heart donor score that reflects experts' perceived risk of allograft failure.
All heart donors reported to Eurotransplant between January 1, 2005 ...and December 31, 2008 (N = 4,110) were used to create a donor score. Based on observed discard rates and using multivariate regression, points were assigned for the following donor factors: age; cause of death; body mass index (BMI); diabetes mellitus (DM); duration of ICU stay; compromised history (drug, abuse, sepsis, meningitis, malignancy, HBsAg(+) or anti-HCV(+)); hypertension; cardiac arrest; echocardiography; coronary angiogram; serum sodium; and noradrenaline and dopamine/dobutamine doses. The donor score was obtained by adding all points. All heart donors reported to Eurotransplant in 2009 were included to validate the score (N = 885).
All donor factors, except BMI, DM and duration of ICU stay, significantly predicted discard. Based on the median value of the score, donors were classified into low-risk donors (LRDs: ≤16 points) and high-risk donors (HRDs: ≥17 points). In the validation set, discard rates were significantly different when comparing HRDs (35%) and LRDs (7%) (p < 0.0001). In addition, the heart donor score was significantly associated with 3-year survival: LRD 81.5% vs HRD 70.0% (p = 0.004).
The heart donor score accurately reflects the likelihood of organ acceptance and predicts long-term patient mortality. Application of this score at time of donor reporting may facilitate donor risk assessment and allow for more appropriate matching of extended criteria donor hearts.
Decision-making when offered a donor heart for transplantation is complex, and supportive data describing outcomes according to acceptance or non-acceptance choices are sparse. Our aim was to analyze ...donor heart acceptance decisions and associated outcomes at a single center, and after subsequent acceptance elsewhere.
This investigation was a retrospective analysis of data obtained from the University of Vienna Medical Center and Eurotransplant centers for the period 2001 to 2015.
Our center accepted 31.8% (699 of 2,199) of donor hearts offered. Unlike other centers, the acceptance rate, with or without transplantation, did not increase over time. Of the donor hearts rejected by our center, 38.1% (572 of 1,500) were later accepted elsewhere. Acceptance rates were twice as high for donor hearts initially rejected for non-quality reasons (339 of 601, 56.4%) compared with initial rejection for quality reasons (233 of 899, 25.9%). Three-year patient survival rate was 79% at Vienna; for donor hearts initially rejected by Vienna for non-quality reasons or quality reasons, it was 73% and 63%, respectively (p < 0.001). Outcomes at other centers after transplantation of grafts rejected by Vienna varied according to the reason for rejection, with good 3-year survival rates for rejection due to positive virology (77%), high catecholamines (68%), long ischemic time (71%), or low ejection fraction (68%), but poor survival was observed for hearts rejected for hypernatremia (46%), cardiac arrest (21%), or valve pathology (50%).
A less restrictive policy for accepting donor hearts at our center, particularly regarding rejection for non-quality reasons or for positive virology, high catecholamine levels, longer ischemic time, or low ejection fraction, could expand our donor pool while maintaining good outcomes.
Oxidative stress contributes to detrimental functional decline of the myocardium, leading to the impairment of the antioxidative defense, dysregulation of redox signaling, and protein damage. In ...order to precisely dissect the changes of the myocardial redox state correlated with oxidative stress and heart failure, we subjected left-ventricular tissue specimens collected from control or failing human hearts to comprehensive mass spectrometry-based redox and quantitative proteomics, as well as glutathione status analyses. As a result, we report that failing hearts have lower glutathione to glutathione disulfide ratios and increased oxidation of a number of different proteins, including constituents of the contractile machinery as well as glycolytic enzymes. Furthermore, quantitative proteomics of failing hearts revealed a higher abundance of proteins responsible for extracellular matrix remodeling and reduced abundance of several ion transporters, corroborating contractile impairment. Similar effects were recapitulated by an in vitro cell culture model under a controlled oxygen atmosphere. Together, this study provides to our knowledge the most comprehensive report integrating analyses of protein abundance and global and peptide-level redox state in end-stage failing human hearts as well as oxygen-dependent redox and global proteome profiles of cultured human cardiomyocytes.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Temporary epicardial pacing wires, implemented in patients during heart transplantation, are routinely removed before discharge. However, in some cases, these wires may remain in situ and are often ...considered as a contraindication for cardiovascular magnetic resonance (CMR) imaging in the future. Therefore, we aimed to provide data about safety and image quality of CMR in these patients.
This is a report on a subpopulation out of 88 patients after heart transplantation that were included in a prospective cohort study and underwent multiple CMR in their post-transplant course. During CMR, patients were monitored by electrocardiogram and all examinations were observed by a physician to document potential adverse events. Additionally, image quality was assessed by an imaging specialist.
Nineteen of 88 patients included had temporary pacing wires in situ. These patients underwent a total of 51 CMR studies. No major adverse event and only one single, mild sensory event could be documented. All CMR studies showed preserved diagnostic image quality. Temporary pacing wires were visible in 100% of HASTE and cine sequences. In less than 50% of the examinations, temporary pacing wires were also visible in T1 and T2 mapping, short tau inversion recovery (STIR), and late gadolinium enhancement (LGE) sequences, without any impairment of image quality.
With a low event rate of only one mild adverse event during 51 CMR examinations (2%), CMR appears to be safe in patients with retained temporary epicardial pacing wires after heart transplantation. Moreover, image quality was not impaired by the presence of pacing wires.
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DOBA, GEOZS, IJS, IMTLJ, IZUM, KILJ, KISLJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, UILJ, UKNU, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Controlled donation after circulatory death (cDCD) has become a standard in liver, kidney, and lung transplantation (LTx). Based on recent innovations in ex vivo heart preservation, heart transplant ...centers have started to accept cDCD heart allografts. Because the heart has very limited tolerance to warm ischemia, changes to the cDCD organ procurement procedures are needed. These changes entail delayed ventilation and prolonged warm ischemia for the lungs. Whether this negatively impacts lung allograft function is unclear.
A retrospective analysis of cDCD lungs transplanted between 2012 and February 2022 at the Medical University of Vienna was performed. The heart + lung group consisted of cases in which the heart was procured by a cardiac team for subsequent normothermic ex vivo perfusion. A control group (lung group) was formed by cases where only the lungs were explanted. In heart + lung group cases, the heart procurement team placed cannulas after circulatory death and a hands-off time, collected donor blood for ex vivo perfusion, and performed rapid organ perfusion with Custodiol solution, after which the heart was explanted. Up to this point, the lung procurement team did not interfere. No concurrent lung ventilation or pulmonary artery perfusion was performed. After the cardiac procurement team left the table, ventilation was initiated, and lung perfusion was performed directly through both stumps of the pulmonary arteries using 2 large-bore Foley catheters. This study analyzed procedural explant times, postoperative outcomes, primary graft dysfunction (PGD), duration of mechanical ventilation, length of intensive care unit (ICU) stay, and early survival after LTx.
A total of 56 cDCD lungs were transplanted during the study period. In 7 cases (12.5%), the heart was also procured (heart + lung group); in 49 cases (87.5%), only the lungs were explanted (lung group). Basic donor parameters were comparable in the 2 groups. The median times from circulatory arrest to lung perfusion (24 minutes vs 13.5 minutes; P = .002) and from skin incision to lung perfusion (14 minutes vs 5 minutes; P = .005) were significantly longer for the heart + lung procedures. However, this did not affect post-transplantation PGD grade at 0 hours (P = .851), 24 hours (P = .856), 48 hours (P = .929), and 72 hours (P = .874). At 72 hours after transplantation, none of the lungs in the heart + lung group but 1 lung (2.2%) in lung group was in PGD 3. The median duration of mechanical ventilation (50 hours vs 41 hours; P = .801), length of ICU stay (8 days vs 6 days; P = .951), and total length of hospital stay (27 days vs 25 days; P = .814) were also comparable in the 2 groups. In-hospital mortality occurred in only 1 patient of the lung group (2.2%).
Although prioritized cDCD heart explantation is associated with delayed ventilation and significantly longer warm ischemic time to the lungs, post-LTx outcomes within the first year are unchanged. Prioritizing heart perfusion and explantation in the setting of cDCD procurement can be considered acceptable.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Donor-specific antibodies (DSA) are integral to the development of antibody-mediated rejection (AMR). Chronic AMR is associated with high mortality and an increased risk for cardiac allograft ...vasculopathy (CAV). Anti-donor HLA antibodies are present in 3–11% of patients at the time of heart transplantation (HTx), with de novo DSA (predominantly anti-HLA class II) developing post-transplant in 10–30% of patients. DSA are associated with lower graft and patient survival after HTx, with one study suggesting a three-fold increase in mortality in patients who develop de novo DSA (dnDSA). DSA against anti-HLA class II, notably DQ, are at particularly high risk for graft loss. Although detection of DSA is not a criterion for pathologic diagnosis of AMR, circulating DSA are found in almost all cases of AMR. MFI thresholds of ~5000 for DSA against class I antibodies, 2000 against class II antibodies, or an overall cut-off of 5−6000 for any DSA, have been suggested as being predictive for AMR. There is no firm consensus on pre-transplant strategies to treat HLA antibodies, or for the elimination of antibodies after diagnosis of AMR. Minimizing the risk of dnDSA is rational but data on risk factors in HTx are limited. The effect of different immunosuppressive regimens is largely unexplored in HTx, but studies in kidney transplantation emphasize the importance of adherence and maintaining adequate immunosuppression. One study has suggested a reduced risk for dnDSA with rabbit antithymocyte globulin induction. Management of DSA pre- and post-HTx varies but typically most centers rely on a plasmapheresis or immunoadsorption, with or without rituximab and/or intravenous immunoglobulin. Based on the literature and a multi-center survey, an algorithm for a suggested surveillance and therapeutic strategy is provided.
•Pre-transplant and de novo DSA affect 3–11% and 10–30% of heart transplant patients.•DSA are integral to antibody-mediated rejection, a major cause of graft loss.•DSA are associated with higher graft loss and mortality post-heart transplant.•DSA also appears to play a contributory role in cardiac allograft vasculopathy.•Immunosuppression should minimize de novo DSA risk but data are sparse.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Allograft pathologies, such as valvular, coronary artery, or aortic disease, may occur early and late after cardiac transplantation. Cardiac surgery after heart transplantation (CASH) may be an ...option to improve quality of life and allograft function and prolong survival. Experience with CASH, however, has been limited to single-center reports.
We performed a retrospective, multicenter study of heart transplant recipients with CASH between January 1984 and December 2020. In this study, 60 high-volume cardiac transplant centers were invited to participate.
Data were available from 19 centers in North America (
= 7), South America (
= 1), and Europe (
= 11), with a total of 110 patients. A median of 3 (IQR 2-8.5) operations was reported by each center; five centers included ≥ 10 patients. Indications for CASH were valvular disease (
= 62), coronary artery disease (CAD) (
= 16), constrictive pericarditis (
= 17), aortic pathology (
= 13), and myxoma (
= 2). The median age at CASH was 57.7 (47.8-63.1) years, with a median time from transplant to CASH of 4.4 (1-9.6) years. Reoperation within the first year after transplantation was performed in 24.5%. In-hospital mortality was 9.1% (
= 10). 1-year survival was 86.2% and median follow-up was 8.2 (3.8-14.6) years. The most frequent perioperative complications were acute kidney injury and bleeding revision in 18 and 9.1%, respectively.
Cardiac surgery after heart transplantation has low in-hospital mortality and postoperative complications in carefully selected patients. The incidence and type of CASH vary between international centers. Risk factors for the worse outcome are higher European System for Cardiac Operative Risk Evaluation (EuroSCORE II) and postoperative renal failure.
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