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Immune rejection remains the major obstacle to long-term survival of allogeneic lung transplants. The expression of major histocompatibility complex molecules and minor histocompatibility antigens triggers allogeneic immune responses that can lead to allograft rejection. Transplant outcomes therefore depend on long-term immunosuppression, which is associated with severe side effects. To address this problem, we investigated the effect of genetically engineered transplants with permanently down-regulated swine leukocyte antigen (SLA) expression to prevent rejection in a porcine allogeneic lung transplantation (LTx) model. Minipig donor lungs with unmodified SLA expression (control group, n = 7) or with modified SLA expression (treatment group, n = 7) were used to evaluate the effects of SLA knockdown on allograft survival and on the nature and strength of immune responses after terminating an initial 4-week period of immunosuppression after LTx. Genetic engineering to down-regulate SLA expression was achieved during ex vivo lung perfusion by lentiviral transduction of short hairpin RNAs targeting mRNAs encoding β2-microglobulin and class II transactivator. Whereas all grafts in the control group were rejected within 3 months, five of seven animals in the treatment group maintained graft survival without immunosuppression during the 2-year monitoring period. Compared with controls, SLA-silenced lung recipients had lower donor-specific antibodies and proinflammatory cytokine concentrations in the serum. Together, these data demonstrate a survival benefit of SLA-down-regulated lung transplants in the absence of immunosuppression.

Objectives: Lack of organ donors demands transplantation of older lung allografts for recipients between 0 and 50 years. So far, it has not yet been investigated whether donor-recipient age mismatch affects long-term outcome., Methods: Records of patients aged between 0 and 50 years were retrospectively reviewed. Donor-recipient age mismatch was calculated subtracting recipient age from donor age. Multivariable Cox regression analyses was performed to assess donor-recipient age mismatch regarding the end points' overall patient mortality, mortality conditioned to hospital discharge, biopsy-confirmed rejection and chronic lung allograft dysfunction. Furthermore, we performed competing risk analysis to analyse if age mismatch affects biopsy-confirmed rejection and CLAD while death being a competing risk., Results: Between January 2010 and September 2021, out of 1363 patients who underwent lung transplantation at our institution, 409 patients fulfilled the eligibility criteria and were included. Age mismatch ranged between 0 and 56 years. Multivariable analysis revealed that donor-recipient age mismatch does not affect overall patient mortality (P = 0.19), biopsy-confirmed rejection (P = 0.68) and chronic lung allograft dysfunction (P = 0.42). There was no difference seen in CLAD (P = 0.166) and biopsy-confirmed rejection (P = 0.944) with the competing risk death (P = 0.765 and P = 0.851; respectively)., Conclusions: Age mismatch between recipients and donors of lung allografts does not affect long-term outcomes after lung transplantation., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: In spite of renal graft shortage and increasing waiting times for transplant candidates, simultaneous heart and kidney transplantation (HKTx) is an increasingly performed procedure established for patients with combined end-stage cardiac and renal failure. Although data on renal graft outcome in this setting is limited, reports on reduced graft survival in comparison to solitary kidney transplantation (KTx) have led to an ongoing discussion of adequate organ utilization., Methods: This retrospective study was conducted to evaluate prognostic factors and outcomes of 27 patients undergoing HKTx in comparison to a matched cohort of 27 patients undergoing solitary KTx between September 1987 and October 2019 in one of Europe's largest transplant centers., Results: Median follow-up was 100.33 (0.46-362.09) months. Despite lower five-year kidney graft survival (62.6% versus 92.1%; 111.73 versus 183.08 months; p = 0.189), graft function and patient survival (138.90 versus 192.71 months; p = 0.128) were not significantly inferior after HKTx in general. However, in case of prior cardiac surgery requiring sternotomy we observed significantly reduced early graft and patient survival (57.00 and 94.09 months, respectively) when compared to patients undergoing solitary KTx (183.08 and 192.71 months; p < 0.001, respectively) or HKTx without prior cardiac surgery (203.22 and 203.22 months; p = 0.016 and p = 0.019, respectively), most probably explained by the significantly increased rate of primary nonfunction (33.3%) and in-hospital mortality (25.0%)., Conclusions: Our data demonstrates the increased rate of early kidney graft loss and thus significantly inferior graft survival in high-risk patients undergoing HKTx. Thus, we advocate for a "kidney-after-heart" program in such patients to ensure responsible and reasonable utilization of scarce resources in times of ongoing organ shortage crisis., (© 2021. The Author(s).)

In this retrospective study, we analyzed the presence of any association of three CD4 + CD25 high regulatory T-cell subpopulations at 3 weeks after lung transplantation with the later incidence of chronic lung allograft dysfunction and graft survival. Among lung-transplanted patients between January 2009 and April 2018, only patients with sufficient T-cell measurements at 3 weeks after transplantation were included into the study. Putative regulatory T cells were defined as CD4 + CD25 high T cells, detected in peripheral blood and further analyzed for CD127 low , FoxP3 + , and CD152 + using fluorescence-activated cell sorting (FACS) analysis. Associations of regulatory T cells with chronic lung allograft dysfunction (CLAD) and graft survival were evaluated using Cox analysis. During the study period, 724 (71%) patients were included into the study. Freedom from chronic lung allograft dysfunction (CLAD) and graft survival amounted to 66% and 68% at 5 years. At the multivariable analysis, increasing frequencies of CD127 low were associated with better freedom from CLAD (hazard ratio for each 1% increase of %CD127 low , HR = 0.989, 95% CI = 0.981-0.996, P = 0.003) and better graft survival (HR = 0.991, 95% CI = 0.984-0.999, P = 0.026). A higher frequency of CD127 low regulatory T cells in peripheral blood early after lung transplantation estimated a protective effect against chronic lung allograft dysfunction, mortality, and re-transplantation., (© 2020 Steunstichting ESOT.)

This retrospective study presents our 4-year experience of preemptive treatment of early anti-HLA donor specific antibodies with IgA- and IgM-enriched immunoglobulins. We compared outcomes between patients with antibodies and treatment (case patients) and patients without antibodies (control patients). Records of patients transplanted at our institution between March 2013 and November 2017 were reviewed. The treatment protocol included one single 2 g/kg immunoglobulin infusion followed by successive 0.5 g/kg infusions for a maximum of 6 months, usually combined with a single dose of anti-CD20 antibody and, in case of clinical rejection or positive crossmatch, with plasmapheresis or immunoabsorption. Among the 598 transplanted patients, 128 (21%) patients formed the case group and 452 (76%) the control group. In 116 (91%) patients who completed treatment, 106 (91%) showed no antibodies at treatment end. Fourteen (13%) patients showed antibody recurrence thereafter. In case versus control patients and at 4-year follow-up, respectively, graft survival (%) was 79 versus 81 (P = .59), freedom (%) from biopsy-confirmed rejection 57 versus 53 (P = .34), and from chronic lung allograft dysfunction 82 versus 78 (P = .83). After lung transplantation, patients with early donor-specific antibodies and treated with IgA- and IgM-enriched immunoglobulins had 4-year graft survival similar to patients without antibodies and showed high antibody clearance., (© 2018 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Experimentally, regulatory T cells inhibit rejection. In clinical transplantations, however, it is not known whether T cell regulation is the cause for, or an epiphenomenon of, long-term allograft survival. Here, we study naïve and alloantigen-primed T cell responses of clinical lung transplant recipients in humanized mice. The pericardiophrenic artery procured from human lung grafts was implanted into the aorta of NODrag -/- /IL-2rγc -/- mice reconstituted with peripheral blood mononuclear cells (PBMCs) from the respective lung recipient. Naïve or primed allogeneic PBMCs procured 21 days post-lung transplantation with or without enriching for CD4 + CD25 high T cells were used. Transplant arteriosclerosis was assessed 28 days later by histology. Mice reconstituted with alloantigen-primed PBMCs showed significantly more severe transplant arteriosclerosis than did mice with naïve PBMCs (p = 0.005). Transplant arteriosclerosis was equally suppressed by enriching for autologous naïve (p = 0.012) or alloantigen-primed regulatory T cells (Tregs) (p = 0.009). Alloantigen priming in clinical lung recipients can be adoptively transferred into a humanized mouse model. Transplant arteriosclerosis elicited by naïve or alloantigen-primed PBMCs can be similarly controlled by potent autologous Tregs. Cellular therapy with expanded autologous Tregs in lung transplantation might be a promising future strategy., (© Copyright 2016 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Donor alloantigen infusion induces T cell regulation and transplant tolerance in small animals. Here, we study donor splenocyte infusion in a large animal model of pulmonary transplantation. Major histocompatibility complex-mismatched single lung transplantation was performed in 28 minipigs followed by a 28-day course of methylprednisolone and tacrolimus. Some animals received a perioperative donor or third party splenocyte infusion, with or without low-dose irradiation (IRR) before surgery. Graft survival was significantly prolonged in animals receiving both donor splenocytes and IRR compared with controls with either donor splenocytes or IRR only. In animals with donor splenocytes and IRR, increased donor cell chimerism and CD4(+) CD25(high+) T cell frequencies were detected in peripheral blood associated with decreased interferon-γ production of leukocytes. Secondary third-party kidney transplants more than 2 years after pulmonary transplantation were acutely rejected despite maintained tolerance of the lung allografts. As a cellular control, additional animals received third-party splenocytes or donor splenocyte protein extracts. While animals treated with third-party splenocytes showed significant graft survival prolongation, the subcellular antigen infusion showed no such effect. In conclusion, minipigs conditioned with preoperative IRR and donor, or third-party, splenocyte infusions may develop long-term donor-specific pulmonary allograft survival in the presence of high levels of circulating regulatory T cells., (© Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: To determine whether the hydroxy-3-methylglutaryl coenzyme A reductase inhibitor pravastatin has a graft-protective effect, we retrospectively analyzed 502 patients who had undergone lung transplantation in Hannover., Methods: Propensity scores have been calculated for each patient and compared between two groups. Cox Hazard analyses were performed for different parameters (e.g., basic parameters of patients, underlying diagnoses, different operations, and important organ functions after lung transplantation). Lung function after transplantation was monitored using repeated measurement analyses. Additionally, conditional Kaplan-Meier survival analyses were used to explore the impact of different diagnoses, the severity of bronchiolitis obliterans, the type of transplantation, and different immunosuppressant regimes on patient survival., Results: The results indicate a strong association between the postoperative administration of statins and the improvement of survival, maintenance of graft (lung) function, and slowing of the onset of bronchiolitis obliterans., Conclusion: These findings suggest a new postoperative therapeutic focus for maintaining graft function.

Objective: Owing to the improved long-term outcome after cardiac transplantation, cardiac allograft vasculopathy or valvular disease is developing late after heart transplantation in a growing number of patients. In this study, we evaluated our results of nonretransplant cardiac surgery in these patients and compared them with those after retransplantation., Methods: Since 1983, a total of 867 heart transplantations have been performed at our institution. Among them, 44 patients underwent nonretransplant cardiac surgery, 4 of them repeatedly. The procedures included 19 coronary artery revascularizations, 20 tricuspid valve procedures, 4 other valvular procedures, 4 aortic operations, and 1 right atrial thrombectomy. Long-term results of these patients were compared with those of 20 patients after late cardiac retransplantation., Results: Indications for nonretransplant surgery included cardiac allograft vasculopathy, tricuspid regurgitation, aortic and mitral valve insufficiency, as well as acute aortic dissection type A. Mean interval between heart transplantation and reoperation was 8.4 years. Mean follow-up was 5.8 years. Early mortality was 4.5% (2/44). The early deaths were caused by intracerebral bleeding and acute rejection. Actuarial survivals at 1, 5, and 7 years were 84%, 64%, and 58%, respectively. In comparison, early mortality in the retransplant group was 20% (4/20) and survivals at the same time points were 70%, 70%, and 47%, respectively., Conclusions: According to these results, we consider nonretransplant surgical options for cardiac allograft vasculopathy and valvular disease a safe and effective therapeutic approach with low early mortality and acceptable long-term results., (Copyright 2010 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.)

Background: This study was designed to analyze the role of postoperative donor cell chimerism for the induction and maintenance of transplantation tolerance in a porcine lung transplantation model., Methods: Left-sided single lung transplantation from major histocompatibility mismatched male donors was performed in 27 female minipigs. All received a 28-day course of pharmacologic immunosuppression using various agents, some in combination with preoperative irradiation. Groups for eventual analysis were strictly defined by outcome, that is, pigs with acute rejection before postoperative day 178 (n=16) were allocated into one group, long-term surviving animals (n=11) into the other. Peripheral blood chimerism was monitored by flow cytometry and real-time polymerase chain reaction. Intragraft chimerism was detected from bronchoalveolar lavage fluid (BALF) by fluorescent in situ hybridization., Results: Blood chimerism peaked 1 hour after transplantation and was significantly higher in the group of long-term survivors at that time. Thereafter chimerism rapidly decreased, but tended to remain higher in long-term survivors. In case of acute rejection donor cells were lost, but remained detectable for up to 36 postoperative months in tolerant animals. In BALF, the percentage of male nuclei was equally high under immunosuppression in both groups. Rejecting animals showed a rapid decrease of Y-bearing cells in BALF after drug withdrawal and an almost complete loss when acute rejection occurred. In tolerant pigs, intragraft chimerism remained detectable throughout the follow-up., Conclusions: This study demonstrates a clear correlation of donor leukocyte chimerism with long-term allograft survival in a porcine allogeneic lung transplantation model.

Background: A simplified conditioning protocol including single-dose preoperative thymic and low-dose whole body irradiation with or without subsequent donor bone marrow transplantation (BMTx) can be applied in porcine lung transplantation. We hypothesized that this protocol would prolong allograft survival., Methods: Left-sided single lung transplantation from major histocompatibility complex (MHC)-mismatched donors was performed in 27 minipigs. Recipients received whole body (1.5 Gy) and thymic irradiation (7 Gy) before transplantation (IRR group, n=6), intravenous immunosuppression with methylprednisolone, cyclosporine, and azathioprine for 27 postoperative days (IS group, n=5) or both (IRR+IS group, n=10). BMTx group recipients were treated with irradiation, immunosuppression and a donor bone marrow infusion on postoperative day 1. Peripheral blood leukocyte phenotype and donor cell chimerism were monitored by flow cytometry. Purified CD25+ T cells from long-term survivors or rejecting animals were used for in vitro MLR suppression assays., Results: Median graft survival was: IRR 12 days, IS 55 days, IRR+IS 239 days, and BMTx 80 days (P<0.0001). Early peripheral blood macrochimerism was substantial in both the IRR+IS and the BMTX group but was lost in all groups after day 80. The frequency and suppressive function of CD4+CD25+ T cells were enhanced in IRR+IS group long-term survivors., Conclusion: Although donor bone marrow infusion was not beneficial in our model, a substantial proportion of the animals treated with irradiation and a 28-day course of immunosuppression accepted their lung allografts long term. The mechanism involved in maintaining allograft tolerance may be based on peripheral T-cell regulation.

Although use of extended-criteria donor organs (ECD) has increased in lung transplantation, their impact on outcomes remains unclear. The Eurotransplant (ET) lung donor score (ELDS) was designed to classify lung donor quality, taking into account donor history, tobacco exposure, age, arterial blood gases, chest x-ray and bronchoscopic findings. This retrospective single-center study evaluates the impact of ECD on graft function and survival. Records of lung allograft recipients transplanted at our institution between 01/2010 and 07/2022 were reviewed. Individual ELDS were calculated from the corresponding ET donor reports. Outcomes were compared between recipients of ideal donors (ELDS 6, Group 1), of intermediate-risk donors (ELDS 7-8, Group 2), and of extended-criteria donors (ELDS 9-15, Group 3). Median (IQR) follow-up was 56 (25-94) months. In total, 273 (19%) out of 1,428 lung-transplanted patients received Group 1 donor organs, 708 (50%) patients Group 2 donor organs, and 447 (31%) patients Group 3 donor organs. Group 2 and 3 recipients were older than group 1 recipients (median age, 53 and 54 vs. 44 years, p<0.001). The need for intraoperative ECMO support (29% vs. 30% vs. 29%, p=0.94), occurrence of primary graft dysfunction grade 3 at 72 hours after transplantation (4.8% vs. 4.7% vs. 6.3%, p=0.47), duration of mechanical ventilation (median 13 vs. 14 vs. 13 hours, p=0.12), and in-hospital mortality (4.4% vs. 4.8% vs. 4.0%, p=0.82) did not differ between Groups 1, 2 and 3, respectively. At 1-year follow-up, no difference in median forced expiratory volume in one second (% predicted) existed between groups 1, 2 and 3 (90 vs. 86 vs. 84, p=0.15), respectively. At 5 and 9 years, graft survival (%) did not differ significantly between groups 1, 2 and 3 (5-year: 74 vs. 69 vs. 71; 9-year: 65 vs. 57 vs. 53, p=0.065), respectively. Freedom from CLAD did not differ between groups 1, 2 and 3 (5-year: 73 vs. 71 vs. 65; 9-year: 63 vs. 58 vs. 54, p=0.077), respectively. At the Cox´s analysis, donor smoking history was associated with worse survival (HR=1.373; 95%CI 1.134-1.662, p=0.001) and with CLAD (HR=1.500; 95%CI 1.225-1.836, p<0.001). ECD lungs constituted one third of our donor pool and their use did not negatively impact the recipient survival and CLAD-free survival. [ABSTRACT FROM AUTHOR]

There is less known about short- and long-term outcomes when sex-mismatched lung allografts are transplanted. Here, we performed a retrospective analysis comparing sex-mismatched with sex-matched patients. Records of patients were reviewed at our institution between May 2011 and September 2022. Four groups were formed: Female to female (F=>F group), male to female (M=>F group), female to male (F=>M group) and male to male (M=>M group) transplanted patients. Categorical variables were analyzed using Chi-square test. Graft survival and freedom from chronic lung allograft dysfunction (CLAD) were compared using Kaplan-Meyer analysis with the log-rank test. During the study period, 1415 patients were transplanted at our institution. 528 patients, 141 patients, 193 patients and 553 patients were in the F=>F group, M=>F group, F=>M group and M=>M group, respectively. There was no statistically significant difference regarding the incidence of primary graft dysfunction (PGD) grade 3 within the first 72 hours after transplant in the different groups (6% vs. 7% vs. 4% vs. 4%; p=0.184). Furthermore, the groups showed no differences in 1-, 6- and 12-year survival (89% vs. 89% vs. 94% vs. 92%; 67% vs. 70% vs. 70% vs. 70%; 51% vs. 55% vs. 57% vs. 46; p=0.67) as well as incidence of CLAD (97% vs. 98% vs. 99% vs. 95%; 66%; vs. 67% vs. 66% vs. 66%; 57% vs. 51% vs. 62% vs. 52%; p=0.565). Donor-recipient sex mismatch does not affect mortality and incidences of PGD grade 3 and CLAD after lung transplantation. [ABSTRACT FROM AUTHOR]

The development of anti-HLA donor specific antibodies detected early after lung transplantation (eDSA) has been associated with antibody-mediated rejection (AMR) and poor graft survival. At our institution, since 2013, successive infusions of IgA- and IgM-enriched human intravenous immunoglobulins (IgGAM, first infusion: 2gr/kg, then 0.5gr/kg once every 4 weeks for a maximum of 6 months) formed the backbone of eDSA therapy. Actually, patients with only evidence of eDSA (possible subclinical AMR) are treated with IgGAM only. Patients with concomitant graft dysfunction (possible clinical AMR) or preformed DSA (positive virtual crossmatch) receive additionally plasmapheresis (PE) or immunoabsorption before the first IgGAM dose, and a single dose of anti-CD20 antibody (Rituximab) thereafter. Aims of this study were to present the 9-year results of the IgGAM-based therapy. Records of patients transplanted between 02/2013 and 10/2022 were reviewed. Outcomes were compared between patients with eDSA and treated with IgGAM (IgGAM group) and without eDSA (control group). Median (IQR) follow-up was 51 (23-79) months. During the study period, among the 1,078 transplanted patients, 270 (25%) patients formed the IgGAM group and 785 (73%) the control group. The remaining 23 (2%) patients (14 patients with eDSA but not treated, and 9 patients treated only with tPE and Rituximab) were excluded. Sixty-five IgGAM patients (24%) showed pre-formed eDSA and 43 (16%) patients showed possible clinical AMR. Median time to eDSA detection was 14 days. At follow-up end, treatment was completed in 246 (91%) patients (still on treatment, n=9; in-hospital deaths, n=4; treatment interrupted earlier as intended by protocol, n=11). In these patients, IgGAM treatment cleared eDSA in 220 (89%) patients, 38 (17%) patients showing eDSA recurrence a median of 15 months after treatment end. In IgGAM vs. control patients and at 5- and 9-year follow-up, respectively, graft survival (%) was 77 vs. 76 and 60 vs. 64 (p=0.83), and freedom from CLAD was 76 vs. 74 and 65 vs. 66 (p=0.74), respectively. After lung transplantation, an IgGAM-based treatment protocol for eDSA yielded high eDSA clearance. Patients with eDSA and IgGAM-treatment have good 9-year graft survival similar to control patients. [ABSTRACT FROM AUTHOR]

Pretransplant sensitization to human leukocyte antigens (HLA) increases waiting list time and mortality in lung transplantation (LTx). Instead of awaiting crossmatch-negative donors, since 2013, our recipients with preformed anti-HLA donor-specific antibodies (pfDSA) have been managed peri-transplant with a combination of repeated IgA/IgM-enriched intravenous immunoglobulin infusions (IgGAM, first infusion 2g/kg, then 0.5g/kg every 4 weeks (wk) to max. 6 months), preceded by repeated plasmapheresis (PE), and a single dose of anti-CD20 antibody (375mg/m2, Rituximab) after the first IgGAM infusion. We hypothesized that the composition of plasma cytokines/chemokines was altered in pfDSA patients due to this treatment compared to DSA-free patients without this peri-transplant immunomodulation. Plasma cytokines and chemokines of subgroups of LTx patients with pfDSA (n=8 of 65) were compared to patients without preformed or de novo DSA (n=26 of 780) before and after LTx. 50 cytokines/chemokines in recipient plasma were quantified before, directly after, 24h, 3, 6wk and 12 months after LTx in these pfDSA+/- subgroups using multiplex assays. Clinical follow-up of all LTx patients was 51 (22-80) months. Of the 1072 LTx patients, 65 (6%) patients exhibited pfDSA, primarily against HLA class II (n=42, 65%), followed by HLA class I (n=19, 29%) and both classes (n=4, 6%), while 780 (73%) did not develop pf or early DSA (control group). In pfDSA vs. control patients, prevalence of primary graft dysfunction grade 3 at 72 hours was 10.8% vs. 4.5% (p=0.036). Graft survival and freedom from chronic lung allograft dysfunction did not differ between groups (9 years, 75% vs. 66%, p=0.41; 65% vs. 65%, p=0.59). The pfDSA treatment protocol resulted in significant changes in the plasma cytokine/chemokine composition with significantly reduced concentrations of several pro-inflammatory factors such as TNF-α, IFN-a2, IL-12p70, CXCL8/9 and FGF-β continuously from pre-Tx to at least 6 months later (all p< 0.05). A treatment protocol based on IgG/AM with PE allowed transplantation of patients with preformed DSA with a 9-year graft survival similar to non-DSA-control patients. The pfDSA treatment caused consistent reduction of multiple cytokines, thereby, potentially contributing to this improved graft survival. [ABSTRACT FROM AUTHOR]

Combined lung and liver transplantation is an uncommon procedure and poses several management challenges. At our institution, since 2005, we have been performing liver transplantation before lung transplantation (liver first strategy), because this strategy might improve the liver coagulopathy thus reducing the risk of bleeding, and spare the successively transplanted lung allograft from the liver reperfusion fluid. Aim of this study was to present our 15-year experience with the liver first strategy for combined lung-liver transplantation. Records of lung-transplanted patients between 01/2005 and 10/2021 at our institution were retrospectively reviewed. Outcomes were compared between patients undergoing combined lung-liver vs. patients undergoing lung-only transplantation. Median (IQR) follow-up was 53 (22-93) months. During the study period, among the 1822 lung-transplanted patients, 17 (0.9%) patients required combined lung-liver transplantation (male sex, n=15; median age, 30 years; lung transplant indication: cystic fibrosis, n=15; lung fibrosis, n=1; porto-pulmonary hypertension, n=1), the remaining 1805 (99.1%) patients undergoing lung-only transplantation. While median lung cold ischemic time (min.) was longer (first lung, 610 vs. 401, p<0.01; second lung, 692 vs. 510, p<0.01) and the intraoperative need for packed red blood cells greater (10 vs. 2 units, p<0.01) in the combined group, only one patient in this group showed primary graft dysfunction (PGD) grade 3 at 72 hours after transplantation (5.9% vs. 5.4%, p=0.61). Prevalence of rethoracotomy for bleeding (18% vs. 10%, p=0.41), temporary dialysis (24% vs. 11%, p=0.12), anti-HLA donor-specific antibodies (DSA, 12% vs. 19%, p=0.35), and in-hospital mortality (12% vs. 7%, p=0.32) did not differ in the lung-liver vs. lung-only transplantation group. Median and hospital stay time (33 vs. 23 days, p<0.01) was longer in the lung-liver group. At-5 years, lung graft survival (62% vs. 66%) and freedom from chronic lung allograft dysfunction (62% vs. 63%) did not differ between the lung-liver vs. lung-only groups (p=0.74 and p=0.71, respectively). Notwithstanding the longer ischemic times and the complexity of the procedure, the liverfirst strategy for combined lung-liver transplantation did not impair lung graft survival and function. [ABSTRACT FROM AUTHOR]

The development of anti-HLA donor specific antibodies (DSA) after lung transplantation has been associated poor graft survival. DSA may develop early after lung transplantation or later, usually when chronic lung allograft dysfunction (CLAD) ensues. Early DSA have recently been considered a product of a memory rather than a de-novo reaction after alloantigen exposure. Aim of this study was to analyse the risk factors for the development of early DSA after lung transplantation. Records of patients transplanted at our institution between 01/2013 and 10/2021 were retrospectively reviewed. Patients were controlled for eDSA every two weeks after transplantation until hospital discharge, using the Luminex single-antigen test (mean fluorescence index threshold, 1000). Multivariable binary logistic regression analysis, including variables with univariable p-value <0.10, was performed to identify factors associated with eDSA. Goodness-of-fit of the model was tested using the Hoshmer and Lemeshow (H-L) test. During the study period, among the 1007 lung-transplanted patients, 275 (27%) patients showed early detectable DSA (preformed, n=56; de-novo, n=254; class I, n=71; class II, n=239). Median (IQR) time to DSA detection was 14 (11-21) days. The binary logistic regression analysis showed that pediatric (<18 years old) transplantation (OR: 2.2, 95%CI: 1.8-2.8, p=0.001), presence of pretransplant HLA antibodies (OR: 2.1, 95%CI: 1.6-2.8, p<0.01), donor lung preservation with Organ Care System (OR: 0.37, 95%CI: 0.14-0.97, p=0.04), and primary graft dysfunction (PGD) score grade 2-3 at 72 hours after transplantation (OR: 1.8, 95%CI: 1.2-1.8, p=0.007) were associated with eDSA detection (H-L statistic, p=0.92). The graft damage and donor antigen exposure provoked by primary graft dysfunction may lead to eDSA production, that should not be considered only a product of a memory but also of a de-novo reaction (Figure 1). [ABSTRACT FROM AUTHOR]

Pretransplant sensitization to human leukocyte antigens (HLA) increases the recipient waiting list time and mortality in lung transplantation. Instead of awaiting crossmatch-negative donors, since 2013, recipients with preformed anti-HLA donor specific antibodies (pfDSA) have been managed peri-transplant at our institution with repeated IgA- and IgM-enriched intravenous immunoglobulin infusions (IgGAM, first infusion: 2gr/kg, then 0.5gr/kg every 4 weeks thereafter to a maximum of 6 months), usually in combination with plasmapheresis (PE) before IgGAM and a single dose of anti-CD20 antibody (375mg/m2, Rituximab) after the first IgGAM infusion. This study presents the 8-year results of this protocol in patients transplanted with pfDSA. Records of patients transplanted at our institution between 02/2013 and 10/2021 were reviewed. Outcomes were compared between patients with pfDSA (pfDSA group) and those without any early DSA (control group). Patients without pfDSA who developed DSA only post transplantation (n=219) were excluded from the analysis. Median follow-up was 47 (21-73) months. Of the 994 transplanted patients, 55 (5%) patients exhibited pfDSA and 721 (73%) did not develop any early DSA. Among these 55 patients, 40 (73%) patients possessed pfDSA against class II HLA antigens and 17 (31%) patients against class I antigens (2 patients against both classes). Twelve (22%) patients showed a positive retrospective CDC crossmatch and 21 (38%) patients developed additional de-novo DSA after transplantation. Forty-four (80%) patients were treated with PE and 45 (82%) patients with Rituximab. At follow-up end, treatment was completed in 45 (82%) patients (still on treatment, n=4; in-hospital deaths, n=2; treatment interrupted earlier as intended by protocol, n=4). In these 45 patients, IgGAM treatment cleared DSA in 33 (73%) patients, with 4 (12%) patients showing the same DSA recurrence. In pfDSA vs. control patients and at 5-year follow-up, respectively, graft survival (%) was 83 vs. 76 (p=0.40) and freedom from chronic lung allograft dysfunction (%) 72 vs. 72 (p=0.62). In lung transplantation, a treatment protocol based on IgGAM allowed transplanting patients with preformed DSA with good 5-year graft survival similar to control patients. [ABSTRACT FROM AUTHOR]