Background: Among solid organ transplant recipients (SOTRs), lung and heart transplant recipients had the highest risk for severe COVID-19.Methods: We present two cases of two heart transplant recipients who underwent transplantation despite perioperative SARS-CoV-2 positivity. We reviewed the clinical records of the two patients. Both patients received a five-day course of Remdesivir (200 mg loading dose, followed by 100 mg daily). Immunosuppression regimens were adapted to reflect standard protocols but included tailored modifications. Thymoglobulin induction was administered at half the usual dose (0.75 mg/kg/day for 72 h), corticosteroids were initiated at a high dose and subsequently tapered to oral prednisone by the end of the first week, and cyclosporine was started on day 3 at 50% of the standard dosage. These adjustments aimed to balance the risk of rejection with the known lymphopenic effects of COVID-19.Results: The postoperative recovery was uneventful, with no complications related to the infection, either systemic or involving the transplanted organ.Conclusion: These cases highlight that transplant candidates with asymptomatic or mildly symptomatic SARS-CoV-2 may safely undergo urgent transplantation when managed with careful antiviral and immunosuppressive strategies. Decisions should be individualized, considering waitlist mortality, infection status, and organ availability. Additionally, these cases underscore the need for a comprehensive review of existing guidelines to inform evolving peri-transplant protocols.Conclusion: These cases highlight that transplant candidates with asymptomatic or mildly symptomatic SARS-CoV-2 may safely undergo urgent transplantation when managed with careful antiviral and immunosuppressive strategies. Decisions should be individualized, considering waitlist mortality, infection status, and organ availability. Additionally, these cases underscore the need for a comprehensive review of existing guidelines to inform evolving peri-transplant protocols.

Antibody-mediated rejection (AMR) is a serious post–lung transplant (LTx) complication with a challenging diagnosis. Histopathological findings associated with AMR include variable degrees of capillary inflammation, endotheliitis, and diffuse alveolar damage/organizing pneumonia. AMR has been historically related to anti-HLA donor-specific antibodies (DSA), while the role of non-HLA antibodies remains debated. We report the case of a 15-year-old male undergoing bilateral LTx for cystic fibrosis. Twenty days later, the patient developed moderate acute cellular rejection (ACR); in samples not affected by ACR, diffuse edema, capillary inflammation, and high p-S6RP expression scores were observed in macrophages, endothelial and epithelial cells. Anti-HLA class II DSA [maximum median fluorescence intensity (MFI): 10434] supported a diagnosis of mixed cellular/humoral rejection. After steroid therapy, DSA markedly decreased (maximum MFI: 1534), and ACR resolved, whereas persistent capillary inflammation and high p-S6RP expression in all cell types characterized sequential biopsies, raising suspicion for ongoing subclinical AMR. The persistence of these morphological features, together with sustained p-S6RP overexpression, prompted extended immunological testing, which revealed markedly elevated antibodies against endothelin type A receptor and angiotensin II type 1 receptor (>40 U/mL) in the patient follow-up. This case underscores the pivotal role of histopathological findings in multidisciplinary decision-making and highlights the importance of extended immunological screening. Our findings further support the emerging pathogenic relevance of non-HLA antibodies in the development and persistence of AMR in LTx recipients. The patient ultimately died 25 months after transplantation from progressive chronic lung allograft dysfunction.

The global shortage of organs for allotransplantation contributes to illicit trade in human organs. While clinical xenotransplantation is proposed as a potential solution to this global shortage, diverse factors contribute to human organ trafficking including global shortages, underdeveloped and under supported organ procurement infrastructures and related legislation, inadequate access to advanced medical therapies or insurance coverage, and poverty and corruption allowing exploitation of vulnerable populations. This article assesses competing predictions regarding the relationship between the advent of xenotransplantation and the global black market for organs. Some argue that a plentiful supply of xenografts will reduce or eliminate the demand that drives organ trafficking. This analysis highlights significant countervailing risks regarding (i) cost, availability, and equitable access; (ii) perceived quality / desirability of an allograft versus a xenograft; and (iii) the emergence of new illicit markets. We conclude that the effect of xenotransplantation on organ trafficking is presently unpredictable but an important metric for success in this field.

BackgroundDespite timely primary percutaneous coronary intervention, coronary microvascular obstruction (CMVO) continues to limit myocardial reperfusion and worsen prognosis in patients with ST-elevation myocardial infarction (STEMI). Agonistic autoantibodies targeting the angiotensin II type 1 (AT1R) and endothelin-1 type A (ETAR) receptors have been associated with CMVO, but whether they directly contribute to microvascular injury remains unclear.MethodsWe prospectively enrolled 287 STEMI patients and evaluated CMVO, left ventricular remodeling, and major adverse cardiovascular events during a median follow-up of 460 days. Immunoglobulins were isolated from a subset of patients with the highest AT1R-AA and ETAR-AA titers and from seronegative controls. Human cardiac microvascular endothelial cells were exposed to patient-derived or control immunoglobulins, with or without pharmacological receptor blockade.ResultsPatients with higher autoantibody titers showed a greater prevalence of CMVO and worse clinical outcomes. In vitro, immunoglobulins from seropositive patients rapidly induced endothelial dysfunction, characterized by cytoskeletal disorganization, junctional disruption, endothelial activation, and increased mitochondrial oxidative stress. These alterations were most pronounced at 24 hours and progressed to reduced cell viability and increased cytotoxicity at 48 hours. Immunoglobulins from seronegative controls had no relevant effects. Blockade of AT1R and ETAR significantly mitigated endothelial injury and oxidative stress.ConclusionsAgonistic autoantibodies against AT1R and ETAR directly damage coronary microvascular endothelium and reproduce key features of CMVO observed in STEMI patients. These findings support a clinically relevant, immune-mediated mechanism of microvascular injury and suggest that receptor antagonism represents a biologically plausible, receptor-dependent mechanism warranting further investigation as a potential microvascular protective strategy in high-risk STEMI patients.

The critical shortage of donor hearts and the limitations of current mechanical circulatory support devices underscore the need for alternative strategies to address end-stage heart failure. Selective endothelial decellularization has emerged as a promising approach to reduce graft immunogenicity by removing donor endothelial cells while preserving myocardial architecture, thereby enabling subsequent repopulation with recipient-derived cells. However, this technique has never been applied to an intact porcine heart. This pilot study aimed to develop an ex vivo model for partial decellularization of the coronary vasculature in whole porcine hearts. Four hearts were perfused through the aortic root using a controlled circuit, applying variable concentrations of sodium dodecyl sulfate (SDS) or trypsin, followed by washout solutions including saline, distilled water, or hypothermic Buckberg cardioplegia. Histological and immunofluorescence analyses were performed on coronary arteries and ventricular myocardium to assess endothelial removal and tissue preservation. Across all experiments, SDS perfusion achieved effective qualitative and quantitative endothelial decellularization of large-caliber coronary arteries while maintaining the integrity of the internal elastic lamina, extracellular matrix, and myocardial structure. The hypothermic cardioplegic washout protocol demonstrated the highest efficacy, with marked loss of endothelial nuclei and decreased expression of CD31, without evidence of myocardial cell depletion. These findings provide preliminary evidence that selective endothelial decellularization of whole porcine hearts is feasible using SDS under controlled hypothermic conditions. This model may represent an essential step toward generating immunologically compatible xenogeneic hearts through subsequent autologous endothelial repopulation. Further studies are required to standardize the protocol, evaluate microvascular compartments, and explore effective recellularization strategies.

The purpose of this white paper is to recommend essential reporting standards for pathologic characterization of kidney and heart xenografts in humans. This proposal is based on the current classifications for human kidney and heart allografts, with additions and caveats relevant to xenografts, primarily derived from nonhuman primate studies and a limited number of organ xenografts in decedent and living humans. Such recommendations should not be regarded as diagnostic criteria, given that many pathologic patterns and mechanisms remain to be fully characterized. While xenograft transplantation continues to evolve, this report serves as groundwork and an initial step toward defining international standards in xenograft histopathology assessment and reporting.

Sex equity in organ donation and access to transplantation represents a key priority of the European Committee on Organ Transplantation of the Council of Europe (CD-P-TO). To increase our knowledge on sex-related differences in transplantation in the Council of Europe Member States, a specifically designed questionnaire was distributed to the CD-P-TO countries. Results confirm that, irrespective of the organ, males represent the majority of patients on the transplant waiting list. For all organs except for heart the time spent on the waiting list was shorter for men compared to women. Women represent the majority of living kidney donors (58%), whilst males are the major source of livers from living donation (54%). Across all organ types, men received 64% of deceased donor organs and 58% of living donor organs. We have found sex-related differences in transplantation activities conducted in the Council of Europe Member States. However, these may be the consequence of the higher incidence of some diseases in men, organ size mismatch, or the greater difficulty in finding immunologically compatible donors in women. At this stage, the CD-P-TO will continue its monitoring activity on this highly relevant topic and possibly extend its commitment beyond sex to include gender related aspects.

Xenotransplantation has entered a phase of accelerated clinical translation, necessitating renewed international consensus on governance, ethics, safety, and regulatory oversight. In September 2025, the International Xenotransplantation Association (IXA), in partnership with The Transplantation Society (TTS) and with engagement from the World Health Organization (WHO), convened a Global Consultation in Geneva to review, update, and harmonise international guidance for clinical xenotransplantation. This IXA consultation marked the twentieth anniversary of the first WHO Xenotransplantation Advisory Consultation in 2005 and built upon the foundational principles established through the Changsha Communiqué (2008, 2011 and 2018) and subsequent IXA and WHO-led initiatives. Responding to rapid scientific advances, including some defined donor genetic standards, improved immunosuppression, enhanced biosecurity, and strengthened infectious disease surveillance, the IXA undertook an 18‑month, structured, evidence‑based revision process. Seven expert working groups, comprising approximately forty internationally recognised specialists from fourteen countries, reviewed developments across source animal standards and biosecurity, clinical trial design and oversight, immunosuppression and patient management, infectious disease risk and surveillance, ethical and legal frameworks, international governance, and emerging technologies. Draft recommendations were further refined through iterative consultation and plenary deliberation at the in‑person meeting held in Geneva, September 2025. The consultation proposed updated Principles and Recommendations directed to WHO, national regulators, investigators and sponsors, and the IXA/TTS communities. Key elements include proportionate risk benefit assessments, robust donor and recipient surveillance, long‑term biobanking and monitoring, transparency and public engagement, harmonised regulatory oversight consistent with existing allotransplantation frameworks, and equitable access to future clinical applications. The revised guidance aligns with contemporary regulatory expectations of major international jurisdictions regulatory authorities including (AEMPS, ANMAT, CONABIA, CONFEPRIS, EMA, FDA, GTAC, HC, IEC, INCUCAI, Medsafe, MFDS, MHRA, MHLW, NMPA, NZGTAC, MFDS, MHRA, TGA); and consolidates international consensus at a critical juncture for the field. This IXA Global Consultation provides an authoritative, forward‑looking framework to support safe, ethical, and globally coordinated clinical xenotransplantation as it transitions from experimental innovation to regulated clinical practice.

Background:Enterococcus faecium bloodstream infections (EF-BSI) cause significant morbidity and mortality in solid organ transplant (SOT) recipients, with the role of vancomycin resistance (VR) remaining controversial as an independent driver. Methods: This was a retrospective cohort study including SOT recipients with EF-BSI at our institution from 2019 to 2023. We used Cox proportional hazards regression to identify predictors of 30-day all-cause mortality. A time-dependent covariate was used to model the effects of receiving targeted, effective antibiotic therapy. Results: A total of 79 patients were included (26.6%, with VR). The overall 30-day mortality was 12.7% (10/79). In univariable analysis, septic shock (Hazard Ratio, HR: 17.1, 95% CI: 3.64-80.8, p < 0.001), the need for Continuous Venovenous Hemofiltration (HR: 6.40, 95% CI: 1.85-22.1, p = 0.003), and a Pitt Bacteremia Score ≥ 2 (HR: 5.17, 95%CI: 1.10-24.3, p = 0.038) were associated with increased mortality, while source control was protective (HR: 0.20, 95% CI: 0.05-0.76, p = 0.018). In the final multivariable model, only septic shock remained an independent predictor of 30-day mortality (HR: 11.4, 95% CI: 1.63-79.5, p = 0.014). VR was not significantly associated with mortality, though the confidence interval was wide and included clinically meaningful effects (HR: 2.07, 95% CI: 0.40-10.6, p = 0.4). Conclusions: In SOT recipients with EF-BSI, 30-day mortality is overwhelmingly driven by the host's physiological response, manifested as septic shock, rather than the VR profile of the pathogen. The early recognition of severe sepsis/septic shock and the aggressive implementation of supportive care and source control measures in this setting are crucial.

Using a deceased donor (DD) to initiate living donor (LD) exchange chains can expand access to kidney transplantation in recipients with an HLA- or ABO-incompatible LD. The Italian DD-initiated kidney paired exchange (DEC-K) program uses a DD kidney to start a chain among incompatible pairs, ultimately returning a LD kidney to the waiting list. We report the first long-term analysis of this approach worldwide. All DEC-K chains performed in Italy between March 2018 and May 2025 were analyzed. Thirty-four chains generated 84 transplants (34 chain-initiating kidneys, 22 from LD, 28 chain-ending kidneys) vs 17 transplants from a conventional kidney paired donation program in the same period. Five-year outcomes were similar between chain-initiating kidney and LD recipients (estimated glomerular filtration rate slope: -2.0 mL/min/1.73 m2/y, P = .37; graft survival: log-rank P = .28). Although this approach diverts blood group O DD kidneys from the general waiting list, potentially affecting nonsensitized candidates, it was designed to address the unmet needs of highly sensitized patients facing years of waiting. In the Italian setting, the DEC-K program successfully initiates LD chains from DD kidneys with outcomes equivalent to LD transplant; implementation should include monitoring of blood group-specific outcomes and a flexible design to accommodate health care system priorities.

Cardiomyopathies comprise a heterogeneous group of myocardial disorders characterized by structural and/or functional abnormalities in the absence of secondary causes of myocardial dysfunction. Although genetic determinants play a central role in many forms of the disease, incomplete penetrance and the frequent absence of identifiable pathogenic variants suggest that additional mechanisms contribute to disease onset and progression. Growing evidence supports the pathogenic role of autoimmune processes in several cardiomyopathy phenotypes. A spectrum of autoantibodies targeting cardiac self-antigens, including structural proteins, intercalated disc components, intracellular proteins such as calreticulin, and G protein-coupled receptors, has been identified in affected patients. Experimental and clinical data suggest that these autoantibodies may exert functional effects on cardiomyocyte signaling pathways and intercellular coupling, thereby promoting maladaptive remodeling, progressive ventricular dysfunction, and an increased risk of arrhythmias. Accordingly, autoantibody profiling may facilitate the identification of biologically distinct cardiomyopathy subsets with potential diagnostic and prognostic implications. From a therapeutic perspective, pathogenic autoantibodies can be removed from patient serum through plasmapheresis or immunoadsorption strategies, and these approaches have been associated with improvements in hemodynamic parameters and clinical outcomes in selected patients.

Background Bioprosthetic heart valves (BHVs) are widely used in cardiac surgery but are limited by structural valve deterioration (SVD). The Translink study showed that immune responses to xenogeneic glycans contribute to SVD. Hyaluronan (HA), a glycosaminoglycan with size-dependent biological functions, has been implicated in inflammation, xenoreactivity, and valve calcification. This study investigated humoral immune responses to HA oligosaccharides in a subgroup of the Translink cohort.Patients and methods Serum samples from 258 BHV recipients and 78 cardiac surgery controls were analyzed by ELISA, and a representative subset was further profiled using a printed glycan array (PGA). BHV recipients were classified with clinically significant SVD (A), as de novo implantation (B1), or long-term without SVD (B2). Controls included mechanical valve replacement or coronary artery bypass patients, either de novo (B1C) or long-term post-surgery (B2C). ELISA quantified IgG and IgM antibodies against HA fragments of increasing length (HA2, HA24, HA84), while PGA mapped fine specificity across HA2-HA40.Results All subjects exhibited measurable baseline anti-HA IgG and IgM antibodies. ELISA revealed a fragment-length dependence, with the shortest fragment, HA2, showing the highest antibody binding, and progressively lower reactivity with longer oligomers. Following de novo cardiac surgery, both BHV recipients and controls showed a transient increase in anti-HA antibodies, peaking at one month and declining within 6-12 months. In contrast, PGA consistently identified HA34 as the dominant immunogenic fragment across all cohorts and time points.Conclusions Anti-HA antibodies are constitutively present in humans, undergo transient amplification after cardiac surgery, regardless of prosthesis type, and display marked fragment-length specificity. Short HA2 fragments predominate in ELISA responses, whereas intermediate-length oligomers, such as HA34, emerge as conserved, immunodominant targets in PGA. These findings extend the Translink paradigm from xenogeneic to matrix-derived glycan immunity and identify anti-HA antibodies as potential biomarkers of postoperative inflammation and tissue remodeling, which could be relevant to SVD.

Antibody-mediated rejection (AMR) is an increasingly recognized form of rejection and cause of graft failure after lung transplantation. AMR has been the focus of extensive research over the past decade. Despite growing awareness and recent advances in our understanding of AMR, outcomes remain dismal with a 2-year survival of only 20%. The International Society for Heart and Lung Transplantation convened a multidisciplinary workgroup of experts in AMR to review the most up-to-date research and clinical experience and to update the 2016 definition. The workgroup was divided into 9 subgroups covering a broad range of topics pertaining to AMR and used the modified Delphi method to synthesize a cohesive summary of the literature. A multidimensional definition was developed to enhance precision by reporting the specific presenting features. This Graft, Antibody, and Pathology (GAP) definition is based on the presence of Graft dysfunction, the presence and characteristics of Antibodies, and Pathological findings. The workgroup emphasized that identifying better treatments for AMR is a critical unmet need and proposed that a more precise definition might allow better management by providing a platform for testing and developing new therapies.

Highly sensitized patients (especially those with a calculated Panel Reactive Antibody ≥ 99.9%) have little to no chances of having access to transplantation. Recently, delisting of human leukocyte antigens has been proposed as a possible strategy to enable transplantation in such patients. In this article, Cucchiari et al. describe the results of a prospective multicenter study based on a delisting strategy. Preliminary results suggest that such an approach has the potential to enable access to transplantation and increase the quality of life of many highly sensitized patients in terminal kidney failure.

Introduction The use of biological heart valves (BHV) is constantly growing but their durability remains a main concern. Structural valve degeneration (SVD) occurs gradually and seems to reiterate, at least in part, the processes described in native valve stenosis. Lipoprotein (a) [Lp(a)] has been described as one of the main triggers of native valve calcification but its association with SVD remains unclear. Objective We aim to determine whether Lp(a) plasma levels and/or the Lp(a) polymorphic sizes, determined by the apolipoprotein (a) [apo(a)] Kringle-IV copy number, were associated with SVD. Method Three hundred and thirty-two patients with BHV for at least 4 years from the Translink study were included. SVD was assessed on echocardiography and computed tomography. Lp(a) concentration was determined by immunoturbidimetry method and the apo(a) Kringle-IV copy number by liquid chromatography-tandem mass spectrometry. Univariable and multivariable models, adjusted for clinically relevant and statistically significant variables, were used to determine the independent association between Lp(a) concentrations and/or apo(a) Kringle-IV copy numbers with SVD. Results Among the 332 patients included in this study, 76 (23%) presented clinically significant SVD on echocardiography. Bioprosthetic valve calcification was significantly higher in patients with versus without SVD (128 [24–259] vs 42 [0–150] mm3, P=0.005). Low apo(a) Kringle-IV copy number was associated with an increased risk of SVD (OR=2.71 [1.34–5.50], P=0.006), but not Lp(a) concentration (OR=0.99 [0.84–1.15], P=0.85). This association remained significant (OR=3.21 [1.31–7.84], P=0.01) after multivariable adjustments including Lp(a) concentration. The analysis of the transprosthetic mean gradient and bioprosthetic valve calcification provided consistent results (all P≤0.05). Conclusion This cross-sectional study from the Translink trial demonstrates the association between Lp(a) polymorphic size and SVD, highlighting a potential therapeutic option to limit the occurrence of SVD in selected patients who underwent AVR with surgical or transcatheter BHV.