To evaluate and summarize the current landscape of peripheral blood monitoring and immunophenotyping of patients following heart and lung transplantation, highlighting recent advances in monitoring which may help to predict and improve clinical outcomes. Immunological contributions to primary graft dysfunction, acute allograft dysfunction, and chronic allograft dysfunction are reviewed. In heart transplantation, novel diagnostic approaches like donor-derived cell-free DNA (dd-cfDNA) and gene expression profiling (GEP) show promise as alternatives to invasive biopsies for detecting rejection. Following lung transplantation, various immune cell populations—including NK cells, T cells, B cells, and regulatory T cells—demonstrate distinct dynamics between peripheral blood and the allograft compartment. Key findings include associations between circulating immune cell phenotypes and chronic lung allograft dysfunction (CLAD), donor-specific antibodies correlating with graft survival, and telomere length serving as a potential biomarker. Immune cells in circulation do not always phenotypically reflect immune cells in the allograft. While some promising markers for allograft dysfunction exist, further studies are needed to correlate them with disease severity and/or progression.
Kidney machine perfusion has moved from a niche preservation tool to a central strategy for using higher-risk deceased donor kidneys. This narrative review examines how contemporary perfusion platforms are reshaping preservation, viability assessment and the emerging concept of organ rehabilitation in kidney transplantation. Continuous hypothermic machine perfusion now has the strongest clinical evidence and reduces delayed graft function in selected deceased-donor grafts. Oxygenated hypothermic perfusion and controlled oxygenated rewarming show increasingly supportive mechanistic and clinical signals, particularly in kidneys at greater ischaemic risk. Normothermic machine perfusion offers direct functional assessment and a platform for ex situ therapy, but the benefits of outcome remain less settled than early enthusiasm suggested. Across platforms, composite assessment models appear more defensible than single perfusion markers. Ex situ perfusion is no longer simply a method of storage. It is becoming a platform for preservation, assessment, rescue of declining kidneys and targeted biological intervention. The next phase of the field will depend on standardised trial design, validated composite viability tools and service models that improve both organ utilisation and post-transplant outcomes.
Lung transplantation is a definitive therapeutic option for selected patients with advanced pulmonary diseases. However, long-term outcomes remain suboptimal, largely driven by immunologically mediated complications, including acute rejection and chronic lung allograft dysfunction, as well as the cumulative toxicity of lifelong immunosuppression. This study was conducted as a systematic review and meta-analysis in accordance with PRISMA recommendations. A comprehensive search of PubMed, Embase, and the Cochrane Library was performed from inception. Randomized controlled trials evaluating maintenance immunosuppressive regimens in adult lung transplant recipients were included. When appropriate, treatment effects were pooled using random-effects models and are reported as risk ratios (RR) with 95
Heart and lung transplantation both face challenges in the diagnosis of acute rejection, which mainly relies on histology with poor interobserver agreement and limited performance characteristics. This limits clinicians’ ability to assess acute rejection, which can be a substantial contributor to graft failure and death. One of the pathways to improve this is through novel molecular diagnostic methods. These methods hold potential to provide mechanistic insights into rejection pathways, reduce rejection assessment variability, reduce biopsy requirements, and improve patient outcomes. This review details the recent advances in this area and discusses their potential role in the future. The most important advances in lung transplantation have been the evolving role of donor-derived cell free DNA (dd-cfDNA) and its ability to detect injured lung tissue, including rejection; the role of lung tissue transcriptomics to characterize rejection in multiple specimen types (transbronchial, endobronchial, and bronchial brush); and exhaled volatile compounds to detect rejection. In heart transplantation, dd-cfDNA and tissue transcriptomics have encouragingly evolved from experimental platforms to clinical use, with some centers shifting their clinical practise. Meanwhile, non-invasive gene expression profiling of peripheral blood has been shown to reduce surveillance biopsies without affecting safety, while other tests like circulating microRNA and extracellular vesicles continue their development. In some heart transplant programs, this is now being used to reduce biopsy frequency, fundamentally changing clinician practice and the patient experience. Thoracic transplantation is changing, with new molecular tests that promise new dimensions of information for clinicians and patients. The future of clinical practice in these areas will likely involve multimodal assessment of conventional clinical tools and next generation molecular tests, in the hopes of helping patients live longer, better lives.
Chronic antibody-mediated rejection (CAMR) is the leading cause of late kidney allograft failure. Despite major advances in diagnostic criteria, molecular profiling, and immunologic risk stratification, no therapy has convincingly demonstrated an improvement in long-term graft survival in patients with CAMR. This review summarizes the evolving definition of antibody-mediated rejection, with an emphasis on chronic active and chronic phenotypes, and critically appraises the current evidence for strategies aimed at prevention, treatment, and monitoring. We examine data on the role of microvascular inflammation and emerging biomarkers in disease progression, and discuss why therapeutic trials in CAMR have largely failed—highlighting factors such as late intervention, irreversible chronic injury, and heterogeneous trial inclusion criteria and clinical endpoints. Until effective therapies for CAMR are established, management should prioritize prevention through optimized immunosuppression and adherence, early detection of alloimmune injury, conservative renoprotective strategies, and enrollment in well-designed clinical trials.
We examined voluntary safety reporting systems in high-reliability medical organizations to identify lessons applicable to the U.S. transplant system. Voluntary, non-punitive reporting systems substantially outperform regulatory oversight in capturing the near misses and low-frequency events that drive genuine learning. Enforcement authority and candid voluntary reporting exist in inherent tension — a condition that limits the U.S. transplant system's learning capacity not from any institutional failure, but from the nature of regulatory authority itself. We propose the Transplant Safety and Learning Network (TSLN), a federally listed Patient Safety Organization operating independently of enforcement structures, open to all members of the transplant team and the patients and families they serve. The TSLN would enable cross-institutional pattern detection for events invisible at the program level. Building it is not merely an operational opportunity — it is an ethical obligation.
Patients with end-stage renal disease often suffer from advanced atherosclerotic calcifications of the aortoiliac vasculature due to hypertension, diabetes and uremia. These aortoiliac calcifications can pose a significant anatomic barrier to successful renal transplant. In this review, we discuss screening strategies for aortoiliac calcification in renal transplant candidates and several surgical approaches permitting renal transplant in the setting of severe aortoiliac disease. Techniques such as iliac endarterectomy, iliac interposition graft, end-to-side iliac extension and sewing the kidney onto an aortobifemoral bypass graft are well-described. Several newer techniques, such as use of endovascular balloons for vascular control, remote endarterectomy, physician-modified fenestrated endografts and placement of the renal allograft upside-down have also been recently described. Innovative surgical techniques can enable successful renal transplant in patients with advanced aortoiliac calcifications that were previously deemed to have anatomic contraindications to transplant.
The 2023 Securing the U.S. Organ Procurement and Transplantation Network Act mandated the most significant governance changes to organ transplantation in decades. This review analyzes the implementation of these reforms, arguing that while the legislation successfully addressed corporate conflicts of interest, it failed to resolve the foundational dynamics that prioritize professional autonomy over public accountability. The separation of the OPTN Board from its legacy contractor created a new entity (INVEST) yet retained a governance structure dominated by industry insiders. This failure to empower non-clinical voices precipitated the mass resignation of patient representatives in 2025. Concurrently, federal oversight has shifted toward aggressive sub-regulatory directives from HRSA. This top-down approach risks exchanging industry capture for bureaucratic overreach and faces legal vulnerability following the Supreme Court’s overturn of Chevron. To restore legitimacy, the OPTN must transition from a self-regulatory model to a public trust framework. Drawing on the governance architecture of the Financial Industry Regulatory Authority (FINRA), this paper proposes a structural requirement where independent public members outnumber industry representatives on the Board. This shift is essential to eliminate capture, ensure fiduciary rigor, and permanently align the system with the public interest.
Artificial intelligence (AI) in healthcare has evolved dramatically from early expert systems, which were initially considered replacements for clinical judgment, to today’s collaborative frameworks that aim to augment physician decision-making. This evolution is particularly crucial in domains such as transplant surgery, where decisions carry irreversible consequences and require the integration of complex, often ambiguous data. Drawing on peer-reviewed literature from 2019 to 2025, we conducted a systematic review that analyzed key elements distinguishing successful human-AI partnerships from those that fail. The ideal balance incorporates human expertise into AI systems through weighted integration approaches, rather than binary accept-or-reject paradigms. This nuanced integration requires the ability to understand and adapt to the unique context of each case, underscoring the complexity and importance of the work of medical professionals and researchers. For transplant surgeons, whose practice exemplifies complex decision-making, current AI approaches built on binary logic struggle to capture the nuanced reasoning required for effective decision-making. Evidence from randomized controlled trials and multicenter validation studies demonstrates how human-AI collaborative systems achieve superior outcomes compared to either human or AI performance alone. This systematic review traces the evolution of human-AI collaboration in medical decision-making, identifies gaps that limit true collaborative teaming, and examines how fuzzy logic systems offer a framework for supporting complex decisions while maintaining the clinical interpretability that surgeons require for confident decision-making
Proteinuria is a post-kidney transplant complication associated with adverse patient and graft outcomes. While proteinuria guidelines in non-transplant chronic kidney disease have adapted to emerging evidence, similar guidelines in transplantation ought to as well. Recent evidence suggests that quantifiable albuminuria, even in patients without detectable proteinuria significantly impacts kidney transplant recipients, increasing odds of graft failure 25-fold, all-cause mortality nearly 5-fold, cardiovascular mortality nearly 7-fold, and malignancy-related mortality more than 8-fold. Such data along with the contemporary paradigm shift in field-changing anti-proteinuric therapeutics have prompted this examination of post-transplant proteinuria. In this review, we aim to refine current understanding of post-transplant proteinuria as well as highlight key broad strategies beyond rejection applicable to the broader audience of nephrologists involved in the care of kidney transplant recipients.
Evaluating lung transplant candidates with underlying systemic autoimmune rheumatic diseases is challenging due to a wide spectrum of extrapulmonary manifestations, leading to variable practice among centers. This article aims to define autoimmune disease activity and treatment failure, discuss post-transplant complications of pre-transplant immunosuppression, propose criteria for timely lung transplant referral, and discuss management of rheumatologic manifestations after lung transplant. The guidelines and rheumatological considerations in lung transplant candidates remain unclear, with poorly understood effects of autoimmune disease on lung transplant outcomes and acceptance criteria for these risks. In this review, we will discuss the important gray areas in the rheumatological considerations for lung transplant candidates, specifically addressing diagnostic uncertainty and therapeutic dilemmas involved, as well as the need for standardization protocols among lung transplant centers on rheumatological evaluation and considerations.
Transplantation activity is low in middle-income countries due to economic constraints and inadequate infrastructure. Several funding models have been developed, including Universal Health Coverage and Public-Private Partnerships (PPP). This review highlights these models in selected countries where programs have achieved financial sustainability and offer transplantation free of cost to patients. Government expenditure on health in middle-income countries ranges from 2.9 to 11.79
Understanding the attitudes and perceptions that healthcare workers (HCWs) hold towards xenotransplantation is necessary to ensure ongoing support in research and clinical settings. To date, there have been no survey studies on HCWs who participated in solid-organ xenotransplantation research, in either the decedent-model or a living patient. Two anonymous surveys were distributed to healthcare workers involved in the clinical management and coordination of pig-to-human xenokidney and xenoheart studies in brain-dead human decedents at a single institution. In total, 58 respondents were included, two-thirds of which exclusively provided direct medical care to the decedent while one-third exclusively provided operational or research support. Results indicated that HCWs are strongly motivated to contribute to xenotransplant research to impact change upon the greater scientific and healthcare community and for personal achievement or satisfaction. While about half of respondents reported at least one apprehension to participation, these apprehensions were abrogated after caring for xenotransplant recipients. Most respondents reported no barriers to future participation, but among those who reported at least one barrier, the risk of zoonosis transmission was the most frequent. Despite reported apprehensions and potential barriers, most HCWs found the experience rewarding, felt that they impacted the overall success of the study, and would assist with future xenotransplant research.
The proinflammatory Interleukin-6 (IL-6) plays a critical role in immune-mediated allograft rejection. Therapeutic targeting of IL-6 has emerged as a novel strategy in the treatment of rejection in the clinic. Herein, we summarize recent approaches utilizing IL-6 targeted therapies in clinical organ transplantation. Two therapeutic agents, Tocilizumab and Clazakizumab (IL-6 receptor and IL-6 monoclonal antibodies, respectively), were used for either desensitization or for AMR treatment. Most studies were in kidney transplant recipients, in addition to fewer heart and lung transplant recipients. While some studies demonstrated favorable outcomes including improved graft function, reduced antibody levels, and improved histopathological features of rejection following Tocilizumab or Clazakizumab administration, other studies did not demonstrate any beneficial effects. There remains lack of consensus on approaches employing IL-6-targeting in combination with currently used immunosuppression. Mixed results obtained maybe attributed to small number of patients studied, associated co-morbidities and variability in biodistribution among transplant patients. Experimental and clinical evidence support therapeutic targeting of IL-6 in transplant recipients. Widespread adoption will require controlled evaluation in randomized clinical trials to validate long-term outcome and potential side effects.
Deceased organ donation remains profoundly underutilized in low- and middle-income countries (LMICs) despite being the cornerstone of self-sufficient transplantation systems. Most LMICs—including India—still depend heavily on living donors because of gaps in legislation, infrastructure, and public acceptance. This review synthesizes global evidence and the Indian experience to identify actionable strategies that can expand deceased donation in resource-constrained settings. Major barriers include inconsistent brain-death determination, weak hospital-based organ retrieval and coordination networks, including limited linkage with centralized allocation systems, limited immunological and preservation facilities, cultural and religious misconceptions, and inadequate family counselling. Several LMICs, particularly India, have shown progress through state-level models (e.g., Tamil Nadu, Kerala, Gujarat) that emphasize trained transplant coordinators, sustained public awareness, and streamlined medico-legal clearances. Internationally, successful frameworks integrate professionalized donor coordination, mandatory brain-death reporting, transparent digital registries, and early adoption of donation after circulatory death (DCD) and machine perfusion. Emerging innovations such as green corridors, drone transport, and structured donor recognition programs further enhance organ utilization. Achieving transplant self-sufficiency in LMICs requires a multi-pillar approach: ethical governance and transparent allocation systems; uniform brain-death and DCD protocols; robust retrieval and immunology infrastructure; continuous training of transplant professionals; and culturally sensitive public engagement. India’s mixed progress illustrates that context-adapted policies, coupled with long-term investments in capacity building and technology, can transform deceased donation from a marginal resource into a dependable, equitable lifeline.
Lung transplantation remains a life-saving intervention for many patients with end-stage lung disease. Given scarcity of donor organs, candidacy evaluation of potential recipients entails an extremely detailed assessment where history of malignancy, at least traditionally, was considered a contraindication. This review details the evolution of recommendations surrounding transplant candidates with pre-existing cancers, explores the complex interplay between predicting cancer risk and weighing it against transplantation benefit, and highlights the existing data on cancer-related outcomes in lung transplant recipients. Advancements in cancer screening, diagnostics, surveillance tools, and treatments have led to a greater number of patients with oncologic history being considered for transplantation. Current expert opinion consensus documents underscore the critical importance of a rigorous evaluation focused on assessing the specific type and stage of pre-existing malignancy and extrapolating risk of recurrence into required disease-free intervals prior to listing. Contemporary practice in eligibility evaluation of patients with pre-transplant malignancies now involves a highly nuanced and meticulously comprehensive approach, balancing the imperative to extend life through transplantation against the inherent risks of cancer recurrence.
Organ procurement organizations (OPOs) carry the responsibility of identifying and managing deceased organ donors and allocating organs from these donors. The transplant system includes multiple other independent organizations, including transplant centers, which the OPOs must collaborate with in pursuit of the shared goal of improving transplant access. Previous quality metrics for OPOs included donation rates per eligible death and aggregate donor yield, while transplant center metrics emphasized recipient outcomes. In an effort to better align OPO metrics with patient-centered outcomes, CMS changed the measures of OPO performance in 2021 to specifically define potential donor deaths and include transplant rate as a metric for the first time. Ensuing criticism of these changes included concerns that utilizing transplant rate as a metric for OPOs is not entirely under the control of the OPO, with upstream influence from donor characteristics and downstream influence from transplant center acceptance practices, but OPO operational practices do meaningfully influence organ utilization. While there are additional concerns that transplant rate as a performance metric may penalize OPOs with a higher risk tolerance, the absolute gains in volume from more aggressive donor pursuit appears to outweigh potential increases in discard or non-utilization. Coupled with offer acceptance as a transplant center metric, utilizing transplant rate as an OPO metric better aligns patient-centered outcomes with OPO metrics and supports the overall goal of the transplant system: translating every viable organ into a transplant.
Invariant Natural Killer T (iNKT) cells are innate-like T lymphocytes bridging innate and adaptive immunity. Their capacity for rapid, potent cytokine secretion and their enrichment in organs such as the liver and lungs position them as critical modulators of allograft outcomes. This review summarizes the current understanding of iNKT cell biology and their multifaceted roles in solid organ transplantation. Recent findings reveal multifaceted roles of iNKT cells in transplantation. They are key early mediators of ischemia-reperfusion injury, particularly in the liver and kidney, and also contribute to alloimmunity. They are also essential for immune defense against opportunistic viral and bacterial infections common in transplant recipients. In the specific context of transplantation, standard immunosuppressive strategies additionally impact iNKT cell numbers and function. Existing evidence has shown that iNKT cells play a crucial role in solid organ transplantation. A better understanding of mechanistic pathways underlying their functional variabilities will facilitate translating iNKT-targeted therapies to benefit graft survival and transplant outcomes.
The lung and gut microbiomes have been associated with many important patient-centered outcomes in respiratory diseases, and these have been further associated with pulmonary immunity. Lung transplant patients are necessarily unique with regards to their microbiome characteristics and their immune responses. The goal of this review is to summarize the emerging literature relevant to of bidirectional relationship of the microbiome and pulmonary immunity, with a focus on data relevant to lung transplant recipients. Lung transplant patients tend to have increased lung bacterial burden and shifts in microbial community composition relative to healthy controls. These lung microbiome changes are linked to important post-transplant outcomes, including primary graft dysfunction, acute rejection, and chronic lung allograft dysfunction. Furthermore, these lung microbiome characteristics—especially having an increased lung bacterial burden or communities dominated by “pathogenic” taxa are associated with a pro-inflammatory pulmonary immune signals in lung transplant patients, despite their concurrent use of immunosuppression. The gut microbiome, through systemic pathways such as short-chain fatty acid (SCFA) production, also appears to influence pulmonary immunity in non-transplant patients, although its role in lung transplant recipients remains underexplored. The lung microbiome remains an important factor in pulmonary immunity after lung transplantation, and the gut microbiome has been implicated as further impacting pulmonary and systemic immunity in non-transplant population. Microbiome-targeted interventions show promise—especially in selected populations—but have not yet been linked with improved patient-centered outcomes. Further research which incorporates adequate clinical context is needed to disentangle which microbiome features and immune signals might be harnessed or targeted to optimize post-transplant care and prolong allograft survival.
