Current Opinion in Organ Transplantation最新文献

Purpose of review: This review examines the epithelial-immune crosstalk in lung transplant ischemia-reperfusion injury (IRI). IRI is the mechanism underpinning primary graft dysfunction (PGD), a clinical syndrome that occurs in nearly one-third of lung transplant recipients associated with increased mortality.

Recent findings: The epithelium is constituted by a diverse array of cells with complex contributions to allograft airway homeostasis. IRI disrupts this balance leading epithelial barrier compromise. However, emerging evidence suggests that epithelial cells are central to the propagation of this initial injury. Epithelial stress responses, including glycocalyx shedding and mitochondrial dysfunction, trigger innate immune activation through the release of DAMPs and stress ligands. Resident macrophages, neutrophils, and NK cells interface directly with epithelial-derived signals to drive inflammation and propagate tissue injury. Additionally, adaptive immune cells, particularly cytotoxic and senescent T cells and B cells, contribute to early and late allograft injury. Novel therapeutic strategies aim to preserve epithelial integrity and modulate immune activation.

Summary: Understanding epithelial-immune crosstalk reveals new avenues for mitigating PGD by targeting epithelial pathways and innate immune effector cells. These insights can inform future therapies to improve lung transplant outcomes and mitigate additional allograft injuries.

Purpose of review: The ischemia-reperfusion injury (IRI) of the bronchial epithelium after lung transplant (LTx) leads to tissue-specific stem cells (TSC) activation, promoting their migration and facilitation of airway remodeling characterized by a chimeric mixture of donor-derived and recipient-derived epithelial cells. This process results in airway epithelial cell chimerism, which we will discuss in this review as having a role in the pathogenesis of chronic lung allograft dysfunction (CLAD) in LTx recipients (LTRs).

Recent findings: In LTx, IRI of the airway epithelium can be significant, contributing to cell death and inflammatory processes. TSCs have been implicated in the pathogenesis of CLAD. In cystic fibrosis LTRs where we can differentiate epithelial cells by cystic fibrosis transmembrane conductance regulator (CFTR) function, integration of recipient-derived cells expressing dysfunctional CFTR protein were discovered even years after the LTx, and this chimerism impacted CFTR function. Recent findings also highlight similarities between pulmonary chronic graft-versus-host disease and CLAD. Animal studies have demonstrated that donor-derived epithelial cells can successfully engraft and aid tissue repair.

Summary: Airway epithelial cell chimerism occurs in LTRs because of the normal human bronchial epithelial repairing mechanisms by TSCs that result from the IRI after surgical implantation of donor lungs. Enhancing donor-derived TSCs may offer a promising therapeutic strategy to promote epithelial repair and reduce the risk of CLAD following LTx.

Purpose of review: Heart failure is a final common pathway for many patients with adult congenital heart disease (ACHD). As such, ACHD heart transplantation is increasingly being considered and performed. Ethical considerations exist at each step in the transplantation process.

Recent findings: ACHD patients face many challenges to successful heart transplantation. A dearth of ACHD cardiologists and many barriers to transplant consideration highlight inequities related to recognition of end-stage disease and timely referral for advanced therapies. Certain vulnerable ACHD sub-groups may more easily elude heart transplant consideration emphasizing injustices for patients such as those transitioning from pediatric to adult care, patients that are under- or uninsured, and those with chronic disabilities. Increased short-term transplant morbidity and mortality requires ACHD cardiologists and heart transplant teams to balance aspects of both beneficence and nonmaleficence when considering who, when, and where to transplant these complex patients.

Summary: Given the rising incidence of ACHD transplantation, centers around the globe are tasked with how to best manage this patient cohort through successful heart transplantation. This review highlights multiple ethical issues in an effort to identify opportunities to provide more accessible, equitable, and standardized advanced cardiac therapies to this unique patient population.

Purpose of review: Persistent disparities in access to kidney transplantation, particularly living donor transplant and preemptive transplant, have gained increasing national attention including efforts to describe their multifactorial root causes. Multilevel structural impediments occurring at the recipient, donor, clinician, and health system level contribute to these disparities. This review overviews these key barriers, as well as recent successful interventions designed to address longstanding disparities.

Recent findings: Several systems-level interventions including the Systems Intervention to Achieve Early and Equitable Transplants (STEPS) study (NCT05014256) may offer effective solutions to address critical roadblocks that lead to living donor kidney transplantation (LDKT) disparities by leveraging health system capabilities, coupled with individually-tailored support. Novel approaches leveraging community-based organizations, tele-health programs that overcome physical and transport related barriers, transplant navigators, and other individuals trained to meet patients' specific needs as they navigate complex transplant journeys, also offer promise. In addition, programs that fast-track complex evaluation requirements through tailored coordination offer promise to reduce racial and ethnic disparities in transplant receipt.

Summary: The success and sustainability of future interventions designed to eliminate longstanding transplant disparities will require concerted investments in multilevel interventions and access-enhancing policies that address the cascade of barriers impacting patients, donors, clinicians, and health systems.

Purpose of review: Heart transplantation referrals in congenital heart disease patients are increasing as this population grows in number, complexity, and disease severity.

Recent findings: We examine short-term and long-term outcomes data with special attention to single-ventricle patients and multiorgan transplantation, including recent advances in combined heart and liver transplantation.

Summary: Given the limited supply of available organs for transplantation, it is necessary to examine heart transplantation outcomes in congenital heart disease patients to better optimize outcomes and ensure equity with noncongenital heart disease patients.

Purpose of review: Ischemia-reperfusion injury (IRI) remains a major challenge in lung transplantation, contributing to early graft dysfunction and negatively affecting long-term outcomes. This review highlights recent advances in the use of mesenchymal stem cells (MSCs) and their extracellular vesicles (EVs) as emerging therapeutic approaches to reduce IRI and improve graft viability.

Recent findings: MSCs exert beneficial effects through paracrine mechanisms, including the release of EVs that carry bioactive molecules such as microRNAs, cytokines, and growth factors. These vesicles play a critical role in modulating the immune response, reducing inflammation, and promoting tissue repair. In preclinical models, MSCs and EVs have been shown to limit neutrophilic infiltration, downregulate pro-inflammatory mediators, and enhance alveolar fluid clearance. Furthermore, the use of ex vivo lung perfusion (EVLP) has emerged as a promising platform for the controlled administration of MSCs and EVs, allowing for targeted intervention prior to implantation.

Summary: Accumulating preclinical data support the potential of MSC- and EV-based therapies to mitigate IRI and improve graft function. Clinical translation will depend on refining delivery strategies, determining optimal dosing, and ensuring reproducibility - particularly when integrated with EVLP protocols.

Purpose of review: Published work evaluating machine perfusion of DCD (donation after circulatory death) liver grafts in situ and ex situ is rapidly evolving, with several landmark studies published in the last 6 months. The central question in DCD liver transplant remains; which strategies most effectively reduce cholangiopathy? This condition, which results in repeated hospital admissions, interventions, re-transplantation and death, is a major deterrent to DCD utilization. This review considers current evidence in the mitigation of transplant cholangiopathy by machine perfusion in DCD liver grafts.

Recent findings: Studies which directly address DCD cholangiopathy as a primary outcome are few in number, despite their critical importance. In systematic reviews, Normothermic Regional Perfusion and Hypothermic Machine Perfusion consistently and significantly reduce transplant cholangiopathy rates. By contrast, the efficacy of Normothermic Machine Perfusion performed at donor or recipient centres is less well described and cautious interpretation is required. The most recent development, namely hypothermic followed by normothermic perfusion, has only now appeared in the literature but appears to offer advantages compared to either technology alone.

Summary: To reduce DCD cholangiopathy, current data best support the use of donor centre NRP or recipient centre HMP. However, utilization is also improved when warm perfusion is involved.

Purpose of review: The Banff 2022 pancreas transplant pathology update is the most comprehensive to date. It has improved the criteria for T-cell and antibody mediated rejection, recognized other clinicopathological differential diagnoses, and addressed the critically important islet failures. Nevertheless, multidisciplinary discussions during and after the meeting showed a need to enhance the real and perceived value of pancreas transplant biopsies. In particular, the occurrence of clinicopathological discrepancies and/or inconclusive biopsy findings, result in considerable uncertainty in clinical and pathology decision making.

Recent findings: The current review expands on the 2022 report by presenting the most common situations leading to an inconclusive diagnosis (Banff "indeterminate" category), a major issue of discussion. The entities discussed herein are: nonspecific infiltrates versus active rejection; residual inflammation after treatment of active rejection; ischemic pancreatitis and peripancreatic reactions in the early posttransplant period; biopsy findings associated with exocrine drainage impairment, and other unusual or nonspecific findings. An algorithm for the evaluation of pancreas allograft biopsies is also presented, that should facilitate the interpretation of morphological findings.

Summary: Systematic integration of essential clinical information with the pathology findings can improve the diagnostic yield of pancreas allograft biopsies and reduce the cases with and "indeterminate" diagnoses.

Purpose of review: Allograft rejection remains enigmatic and elusive following pancreas transplantation. In the absence of early technical pancreas graft failure, pancreas allograft rejection is the major cause of death-censored pancreas graft loss both short- and long-term. Despite this circumstance, there are variations in the diagnosis and treatment of pancreas rejection. In this article, we summarize recent literature, review common practices, and discuss various management algorithms.

Recent findings: Although pancreas allograft biopsy is the gold standard for the diagnosis of rejection, not all transplant centers have the capability to perform pancreas allograft biopsy. Some centers depend on clinical or laboratory parameters exclusively or rely on dysfunction or biopsy of a simultaneous kidney allograft as a marker for pancreas allograft rejection. New biomarkers are evolving to assess the risk for rejection and may help to diagnose early rejection. In the future, the use of machine learning algorithms and artificial intelligence may play a role identifying patients at risk and detecting pancreas rejection without performing a pancreas allograft biopsy.

Summary: Despite decades of experience in pancreas transplantation, the diagnosis and management of pancreas rejection remains challenging. Emerging biomarkers and machine learning algorithms are needed to mitigate immunological complications and guide immunosuppression in these patients.

Purpose of review: For those with insulin dependent diabetes mellitus and renal failure, both simultaneous pancreas and kidney (SPK) and pancreas after kidney (PAK) transplant can free the recipient of renal replacement and insulin therapies and provide survival advantage over ongoing dialysis and diabetes. Yet, pancreas transplants are notably declining in the United States, particularly for PAK.

Recent findings: Pancreas transplant continues to provide better glycemic control than all present medical therapies. Outcomes for both SPK and PAK also continue to improve, and overall patient survival for both SPK and PAK are similar, excellent, and superior to all other transplant or medical options. SPK is associated with better pancreas allograft survival, but this gap is narrowing for PAK, and the best kidney allograft survival is achieved with living donor renal transplant (LDRTx) and PAK.

Summary: PAK remains a viable and successful treatment for uremia and insulin dependent diabetes, and, particularly when following a LDRTx, can confer the additional benefits associated with LDRTx and preemptive transplant. To achieve insulin and dialysis independence, either LDRTx followed by PAK (if a living donor is available) or SPK should be offered to candidates with appropriate indications.