IntroductionMany potential organ donors are not referred to the transplant coordination, constituting potential missed referrals.MethodsIn this retrospective analysis, we explored risk factors for potential missed referral among patients suffering from acute brain injury, who were admitted to a 32-bed mixed intensive care unit (ICU) between 2018 and 2023 and died after hypoxic-ischemic encephalopathy, traumatic brain injury, or subarachnoid hemorrhage (SAH). Patients with absolute contraindications for donation were excluded. Each patient was categorized as “actual donor”, “medical refusal”, “personal refusal”, or “potential missed referral”. The primary outcome was the potential missed referral rate.ResultsOf 183 potential donors, 101 (55%) were referred and 82 (45%) were not; on ICU admission, patients in the potential missed referral group were older, had higher severity scores, more comorbidities, and were less likely to have a diagnosis of SAH. In a binomial logistic regression analysis, older age and chronic obstructive pulmonary disease were independent predictors of potential missed referral; donation after brain death and SAH were associated with higher referral rates.ConclusionsThis audit identifies areas for improvement to expand the donor pool, including greater recognition of the donor potential of critically ill patients with extra-neurological complications, even in the presence of older age and comorbidities.
BackgroundDuring ex vivo lung perfusion (EVLP), perfusate pH, electrolyte, and glucose concentrations often deviate from physiological ranges. We evaluated the effect of a corrective solution on maintaining these parameters within physiological limits during 12 h of EVLP in a porcine model.MethodsTwelve porcine lung blocks were harvested and cold-preserved before undergoing 12 h of normothermic EVLP. Lung blocks were randomly assigned to two groups based on the perfusate replacement strategy. All lungs were perfused with Steen solution, mean priming volume was 1,525 ± 340 and 1,325 ± 232 mL, with 100 mL (5%–9%) replaced every two hours by either fresh Steen solution (standard group, n = 6) or a modified solution designed to restore physiological composition (corrected group, n = 6). Perfusate electrolytes, glucose, cytokines, pH, partial oxygen pressure (PO₂), pulmonary vascular resistance (PVR), and compliance were measured. After EVLP, left lungs were transplanted during 4 h into donor-related pigs, while right lungs were analyzed by histology and electron microscopy.ResultsPerfusate correction successfully maintained electrolyte, pH, and glucose levels within target ranges during EVLP. The corrected group demonstrated higher lung compliance and oxygenation, reduced edema, more hyaline membranes, and a greater density of Kohn's pores after EVLP. PVR was similar between groups, and no significant difference in ΔPO₂ was observed post-transplantation.ConclusionMaintaining physiological perfusate composition improved lung function during 12-hour EVLP in swine; however, no post-transplant benefit was observed. Further studies are warranted to assess the impact of this strategy during prolonged EVLP and to compare it with alternative approaches.
IntroductionWhile kidney transplant disparities are well-documented, little is known about disparities in the evaluation process after referral. Electronic dashboards interfacing with electronic health records can disaggregate patient data to identify potential avenues for reducing disparities. This cross-sectional study assessed contextual and design factors that would inform implementation of an ‘Equity Dashboard’ at one transplant center.MethodsClinicians, implementation science experts, and patients were interviewed. Qualitative data were analyzed using thematic analysis guided by the Consolidated Framework for Implementation Research. Quantitative data comprised primarily descriptive survey data collected during interviews.ResultsTwenty clinicians/experts and 23 patients participated. Perceived facilitators included: Inner Setting constructs of mission alignment, culture, tension for change, compatibility, and structural characteristics; and Individual Characteristics construct of high-level leaders. Dashboard alignment was expected with institutional commitment to patient-centered care, center workflow, and leadership support. Perceived barriers included: Intervention Characteristics construct of costs; and Inner Setting constructs of access to knowledge and information, information technology infrastructure, and work infrastructure. Financial costs were expected to support information technology development, staff training and time, and interventions arising from dashboard findings.ConclusionsOur findings suggest that perceived barriers were largely modifiable while perceived facilitators were immutable and integral to the institution, which would facilitate dashboard implementation. Future research will evaluate dashboard implementation on patients’ transplant access.
BackgroundSodium-glucose cotransporter-2 inhibitors (SGLT2i) are established therapies in chronic kidney disease (CKD), but comparative data in kidney transplant recipients (KTR) remain limited.MethodsWe retrospectively matched 100 KTR receiving SGLT2i to 100 controls not receiving SGLT2i and assessed body mass index (BMI), HbA1c, urine albumin-to-creatinine ratio (uACR), estimated glomerular filtration rate (eGFR), serum potassium, RAAS inhibitor use, blood pressure, and safety outcomes at 6 and 12 months. Furthermore, we compared the Jaffé and enzymatic methods to examine the effect of SGLT2i-associated glucosuria on urinary creatinine measurements and the resulting uACR.ResultsBMI decreased in the intervention group and increased in controls; the overall adjusted between-group difference across follow-up remained statistically significant. Descriptive between-group differences in HbA1c were observed at 6 and 12 months, but were not confirmed after multivariable adjustment. Neither uACR nor eGFR differed significantly at 12 months, despite an initial decline in eGFR at 6 months. Serum potassium remained stable over time. Hyperkalemia was associated with lower eGFR, but not with SGLT2i treatment, and RAAS inhibitor persistence did not differ between groups. No statistically detectable differences or clear new safety signals were observed for blood pressure, urinary tract infections, cardiovascular events, or hospitalizations during follow-up. Jaffé-based creatinine measurements were lower than enzymatic measurements, increasing calculated uACR by approximately 8.5% (p < 0.001), with rare albuminuria stage reclassification.ConclusionsSGLT2i use was associated with favorable metabolic changes, particularly a reduction in BMI, without evidence of increased potassium-related risk. No improvement in graft function or albuminuria was observed over 1 year. SGLT2i-associated glucosuria systematically increased Jaffé-based uACR estimates, although clinically relevant albuminuria reclassification was uncommon.
BackgroundUrinary tract infection (UTI) including extended-spectrum β-lactamase (ESBL)-producing organisms is a common early complication after kidney transplantation. Increasing prevalence of ESBL may adversely affect graft and patient outcomes. This study aimed to evaluate the incidence, timing, predictors, and outcomes of UTI, including ESBL infection, after kidney transplantation.Materials and methodsWe retrospectively studied 1,804 adult kidney transplant recipients (2016–2024) at a tertiary center. UTIs were analyzed for incidence, timing, microbiology, and predictors using multivariable logistic regression. Outcomes included rejection, graft loss, and mortality. ESBL and non-ESBL UTIs were compared, and long-term outcomes assessed using Cox regression.ResultsUTI occurred in 693 recipients (38.4%) within the first year post-transplant with 57.4% occurring within 30 days and 84.2% within 90 days. UTIs were more common during ureteric stent indwelling than after removal (64.3% vs. 35.7%). Independent predictors included female sex, older age, deceased donor transplantation, pre-transplant UTI, and post-transplant urological complications. ESBL UTI were identified in 47.9% of patients and were associated with earlier infection, higher recurrence rates and occurred more frequently during stent indwelling (69.0% vs. 60.1%, p = 0.015). UTI was associated with higher rejection, graft loss, and mortality (p ≤ 0.005). ESBL UTI further increased rejection and graft loss. In adjusted analyses, ESBL UTI independently associated with death-censored graft loss (aHR 2.10, p = 0.047) and mortality (aHR 2.17, p = 0.025).ConclusionsUTIs are common early after kidney transplantation, particularly during ureteric stent indwelling. ESBL infections are independently associated with adverse graft outcomes and mortality, supporting targeted surveillance, antimicrobial stewardship, and ureteric stent management optimization.
IntroductionRecent ILTS guidance supports liver transplantation for patients with very small intrahepatic cholangiocarcinoma. This guidance was informed mainly by North American and European data. The applicability of these guidelines to the region of Australia and New Zealand is unknown.MethodsA retrospective study was performed to measure clinical outcomes of liver transplantation in the ANZ region to ascertain the applicability of this new guidance to this region. Historic patients having undergone LT for known cholangiocarcinoma or incidentally detected cholangiocarcinoma or mixed type hepatocellular-cholangiocarcinomas on explant histology were identified via a national registry. Data was inputted from all transplant units within the ANZ region.ResultsWe found that 64 patients had either knowingly or unknowingly been transplanted for cholangiocarcinoma or mixed type hepatocellular-cholangiocarcinoma in our region.DiscussionOverall survival for patients with very small intrahepatic cholangiocarcinomas was 80%, in line with the current international data. We also report 5-year overall survival for patients with incidentally detected mixed tumours on explant histology was 68%.
Organ donation and transplantation has been one of the most important parts of the modern healthcare system that deals with the end-stage organ failure and enhances quality of life and patient survival. But the existing problems of donor scarcity, lack of efficiency in donors usage, mismatches in different organs, regional imbalance, logistic problems and uncoordinated data sharing system have been still a hindrance in the success of the transplantation systems and it is a critical observation of the present situation in the field of organ donation and transplantation which is justified by data analysis of the tendencies in the usage of the donors, tendencies in organ transplantation and regional differences. The paper also outlines the major challenges in the current systems and the new technologies that will be able to revolutionize the transplantation processes such as Artificial Intelligence, Blockchain, Internet of Medical Things (IoMT) and Big Data Analytics. At the same time, new technologies that would help to extend the “liveness” of organs are also carefully analysed as potential ways to simplify the choices, improve the transparency and logistics. While there are solutions to these technologies, some barriers to the technologies are interoperability, governance, ethical issues and the availability of infrastructure. Lastly, the paper provides the research directions in the future, which revolve around convergence of heterogeneous technologies, development of interoperable data ecosystems and the necessity of having equitable and patient-centered transplantation systems. Overall, this review provides an in-depth opinion of the problems, innovations, and directions that need to be introduced to transform organ donation and transplantation into a more efficient, transparent, and accessible healthcare sector on the international scale.
Hypoglycemia is a frequent finding after simultaneous pancreas–kidney (SPK) transplantation, but its etiology is often multifactorial and challenging to interpret. We report a rare case of late-onset severe hypoglycemia secondary to a neuroendocrine tumor arising in a pancreatic allograft. A 60-year-old man with type 1 diabetes mellitus underwent SPK transplantation in 2007 with immediate graft function and long-term metabolic stability. Ten years post-transplant, partial pancreatic graft dysfunction and progressive vascular complications were noted. In 2024, 17 years after transplantation, the patient developed recurrent, documented hypoglycemic episodes despite withdrawal of glucose-lowering therapy, with fasting plasma glucose values as low as 40 mg/dL and a marked reduction in HbA1c. Biochemical evaluation suggested endogenous hyperinsulinism, with elevated chromogranin A levels. Imaging studies revealed a large hypervascular mass within the pancreatic graft, with high somatostatin receptor expression on 68Ga-DOTA-TOC PET-CT. Histology from biopsy and subsequent total graft pancreatectomy confirmed a well-differentiated grade 2 neuroendocrine tumor with focal insulin expression, consistent with insulinoma. Surgical resection resulted in complete resolution of hypoglycemia. This case highlights the need to consider rare but clinically significant causes of hypoglycemia in SPK recipients and underscores the importance of a comprehensive, multidisciplinary diagnostic approach integrating continuous glucose monitoring, biochemical markers, and advanced imaging.
BackgroundChimerism analysis is used in hematopoietic stem cell transplantation (HSCT) to evaluate donor engraftment and assess underlying disease status. Practices vary greatly amongst Canadian transplant centres, and currently, there are no consensus guidelines for testing methodology, time points, cellular source and clinical interventions.ObjectivesTo review the current chimerism practice patterns for Canadian transplant centres and review current literatureStudy designWe surveyed members of Cell Therapy and Transplant Canada (CTTC) via a web based application regarding chimerism practices nationwide with approximately half of all transplant centres responding.ResultsThe majority of centres used similar chimerism laboratory methodologies, though we identified key areas of heterogeneity across transplant centres, namely in the time points for testing and the cellular lineages evaluated. Implications and management of mixed donor chimerism also varied between centres resulting in variability of interventions.ConclusionsReview of current chimerism testing literature highlighted the improving sensitivities of novel testing methods available as well as testing specific cellular lineages to evaluate ongoing donor hematopoiesis. Our survey emphasizes the importance of advocating for a national standard in chimerism testing, and subsequent management based on chimerism results, to better inform clinical practice and to aid in development of prospective research.
Machine perfusion (MP) has transformed liver transplantation by enabling organ reconditioning, extending preservation times, and providing a dynamic platform for graft quality assessment. The ability to evaluate organ viability represents one of the most clinically impactful applications of this technology. As different perfusion modalities develop, distinct strategies have emerged to characterize graft viability. However, despite the growing evidence, significant heterogeneity remains in the parameters and thresholds employed, varying between each MP modality, as well as between centers. This review provides a comprehensive and critical synthesis of available evidence on viability assessment during each perfusion modality, and discusses promising new strategies in the race to the holy grail of viability assessment: prevention of both primary non-function (PNF) as well as the prediction of ischemic cholangiopathy (IC), so as to achieve tangible benefits in patient-centered outcomes.
Under the auspices of the International Society of Vascularized Composite Allotransplantation (ISVCA), a section of the Transplantation Society (TTS) that promotes and encourages research and training in the field of vascularized composite allotransplantation (VCA), the 4th Chauvet Workshop was convened in conjunction with the biennial meeting of the ISVCA from 27–29th June 2025 in Helsinki, Finland. The Chauvet workgroup recognizes the importance of psychological evaluation and management in VCA and works to provide an interdisciplinary platform for the development of psychosocial guidelines for the field. For the first time this workshop was conducted jointly with the ISVCA biennial congress, facilitating wider attendance, and discussions between different units and across disciplines. Three main areas were discussed; outcomes and lessons learned, qualitative research approaches and patient reported outcome measures (PROMS), and the role of team science in complex care models. We also heard an update from patient advocate Vasyly Rohovyy, on the progress being made to develop a VCA patient support and advocacy community. Here we summarize these discussions.
Tacrolimus commonly causes tremor as a side effect, although the relationship between tremor and tacrolimus drug levels is not well established. This work presents the development of a smartphone-based tremor assessment to explore whether tremor features are associated with tacrolimus trough concentrations, including whether individualized models show promise in tremor-sensitive kidney transplant patients. Using smartphone accelerometers, an app was created to record resting and postural tremors in transplant recipients during routine follow-up visits. Tacrolimus trough concentration and doses were recorded at each visit. We evaluated associations between tremor features and tacrolimus trough levels and, in exploratory analyses, assessed regression models both at the cohort level and within individuals with sufficient longitudinal data. Sixty-nine kidney transplant recipients were included. Correlations were found between self-reported tremor severity and tremor features, but no significant association was observed between tacrolimus trough concentration and tremor features at the cohort level (ρ = 0.022, p = 0.447). Population-level regression models showed poor predictive performance. post-hoc exploratory individualized models among patients with adequate longitudinal data (n = 8) provided an averaged root mean squared error of 2.33 ± 1.42 µg/L; three patients achieved root mean squared errors below 1.3 µg/L. Smartphone tremor features did not support population-level prediction of tacrolimus trough concentrations in kidney transplant recipients. Exploratory individualized regression models yielded potentially useful performance in a small subset; consistent with heterogeneity in tacrolimus tremor severity. These findings are hypothesis-generating; larger prospective studies should focus on identifying and validating tremor-sensitive patients for individualized approaches.
Ethical considerations in facial transplantation have been widely discussed for more than twenty years, preceding the technical realization of the procedure in 2005. With more than 50 face transplants performed to date in adults worldwide, considerations are evolving beyond risks and benefits toward questions of equity and sustainability. Yet, issues of informed consent, the risk of lifelong immunosuppression, graft lifespan, and metrics for success continue to prompt dialogue, especially for certain patient populations. In this Perspective, we combine our clinical experience with a synthesis of the existing evidence and propose that emerging adults, characterized as individuals aged 18–25, be given particular consideration. Emerging adults occupy a middle ground between adolescence and established adulthood. This formative life stage has a profound impact on an individual's sense of identity and social integration. Emerging adults stand to benefit significantly from facial transplantation precisely because of the key developmental nature of this stage, yet ongoing cognitive development presents challenges for judgement and decision-making that can complicate care for this population and impact outcomes. Given the complexity of facial transplantation and lifelong commitment to follow up required for face transplant recipients, it is critical to understand potential challenges for decision-making and obstacles to adherence that individuals may face in this developmental life stage. Recognizing emerging adults as a patient population with specific support needs will enable face transplant programs to offer tailored supports to improve outcomes for this transformative procedure in emerging adulthood.
Post-transplant lymphoproliferative disorder (PTLD) is a serious and heterogeneous neoplastic complication of solid organ transplantation (SOT), arising in the setting of sustained pharmacological immunosuppression. This review is specifically focused on PTLD in the SOT setting; PTLD after hematopoietic stem cell transplantation (HSCT) differs substantially in risk factors, pathogenesis, and management, and is beyond the scope of this work. PTLD incidence ranges from 1% to 20%, depending on the grafted organ, with the highest per-procedure rates in intestinal and multiorgan transplants, and the highest absolute case burden in kidney recipients, given transplant volume. PTLD demonstrates a bimodal temporal distribution: an early, predominantly EBV-driven peak at 12-24 months post-transplant, and a late peak at 5-10 years, with a higher proportion of EBV-negative cases. Contemporary evidence suggests a possible decline in early EBV-positive PTLD with improved surveillance, while late-onset EBV-negative PTLD is stable or increasing. EBV establishes latency type III in PTLD-associated B cells, driving proliferation through viral oncoproteins LMP1 and EBNA2. The latency program correlates with histological category and clinical behavior: latency III predominates in early lesions and polymorphic PTLD with strong EBER expression, whereas EBV-negative monomorphic PTLD displays greater genomic complexity, resembling de novodiffuse large B-cell lymphoma (DLBCL), with frequent TP53 mutations and chromosomal gains. The WHO 2022 and ICC 2022 frameworks define four histopathological categories-non-destructive lesions, polymorphic PTLD, monomorphic PTLD, and classic Hodgkin lymphoma (CHL)-type PTLD-each with distinct morphological, immunophenotypic, EBER, and clonality profiles that directly determine treatment intensity. Management follows a sequential strategy: immunosuppression reduction (ISR) as the mainstay first step, followed by rituximab, then chemoimmunotherapy (R-CHOP) for refractory or high-risk disease, with PET/CT-based response assessment using Lugano criteria at each decision point. Tabelecleucel, an allogeneic EBV-specific cytotoxic T-lymphocyte (CTL) product, represents the first approved cellular therapy for refractory EBV-positive PTLD. Immune checkpoint inhibitors carry unacceptably high organ rejection rates and are not recommended for standard PTLD management. Key unmet needs include standardizing EBV surveillance thresholds for preemptive intervention, biomarker-driven risk stratification (PD-L1, LMP1, tumor EBV viral load), and prospective multicenter data on novel immunotherapy combinations in immunosuppressed transplant recipients.
Uterine vascularized composite allotransplantation (VCA) represents one of the latest developments in the field of transplant surgery and treatment of uterine-factor infertility. Unlike other forms of VCA, uterine transplantation involves a temporary allograft, pregnancy-associated physiologic and pharmacokinetic changes, and complex maternal-fetal immunologic interactions, creating distinct challenges in immunosuppression management. Herein, we perform a comprehensive review of the latest and relevant literature on immunosuppressive strategies in the context of VCA and pregnancy, with particular emphasis on their relevance to uterine VCA. Evidence from solid organ transplantation, autoimmune disease, and reported uterine transplant protocols was synthesized to inform stage-specific management strategies. Available data support corticosteroids, calcineurin inhibitors, azathioprine, and hydroxychloroquine as pregnancy-compatible agents, whereas mycophenolate mofetil, methotrexate, and cyclophosphamide remain contraindicated due to teratogenicity. Pregnancy-related pharmacokinetic and pharmacodynamic changes significantly influence drug exposure and necessitate individualized dosing and close therapeutic monitoring. Emerging evidence suggests that pregnancy-associated immune modulation, including regulatory T-cell expansion and microchimerism, may reduce rejection risk, although this remains incompletely characterized. Based on best available evidence, we present a summary for immunosuppressive management spanning induction, preconception optimization, pregnancy, delivery, and postpartum graft removal. Future priorities include development of noninvasive rejection monitoring, precision pharmacokinetic modeling, and tolerance-inducing strategies to improve maternal, fetal, and allograft outcomes in uterine transplantation.
IntroductionChronic kidney disease (CKD) has become a significant global health challenge as patients frequently progress to end-stage renal disease leading to kidney transplantation. Anatomical variations of the renal vascular structure may affect donor candidates, surgical management, and graft success, making it important to consider in transplantation. Although the use of anatomically complicated grafts is growing, differences in vascular pattern continue to impact clinical decision-making.ObjectiveTo investigate the anatomical features of the renal vasculature and determine its clinical significance for kidney transplantation and their effect on surgical complexity and transplant outcomes.MethodsNarrative literature review was performed through PubMed, Scopus and Google Scholar. Articles were included if they were related to kidney vascular anatomy, imaging evaluation, surgical methods, and transplant results. Literature: Included in this review were historical and relevant secondary studies to offer a global perspective of the latest developments in renal transplantation practice.ResultsA large body of studies have explored these renal vascular variations with up to 30% of people having at least two renal arteries, and venous variations such as retroaortic or circumaortic renal veins. These variations can lead to a more complex surgery and duration of operation, as well as a higher chance of development of early complications (delayed graft function or vascular thrombosis) due to ischemia-induced complications. Yet evidence is currently accumulating that, with sound preoperative imaging and surgical precision, the long-term prognosis of grafts and patient outcomes is similar to that of standard vascular anatomy graft. Developments in imaging modalities, especially computed tomography angiography, have greatly advanced both preoperative detection and surgical planning.ConclusionSuch renal vascular variations should not automatically preclude transplantation and should not be considered as an adverse event when donating or transplanting kidneys. Anatomically complex grafts can be successfully used, with careful preoperative assessment, multidisciplinary planning and modern surgical techniques. More standardized reporting and more recent studies are required to optimise donor utilisation and thereby optimize transplant success.
IntroductionTacrolimus (Tac) is highly bound to erythrocytes, with less than 1% present in the pharmacologically active unbound fraction. In anemia, whole-blood trough concentrations may underestimate effective exposure. Hematocrit (Hct) adjustment has been proposed but clinical outcome data are limited.MethodsWe conducted a single-center retrospective cohort study of adult liver transplant recipients (2018 to 2022) to examine the relationship between Hct-adjusted Tac and early clinical outcomes. Tac troughs, Hct, and serum creatinine were collected for 90 days. Hct-adjusted Tac was calculated as (0.45 ÷ Hct) × total Tac. The difference between adjusted and measured Tac (delta Tac) was used to represent anemia-related underestimation and modeled as a time-varying covariate in Cox regression for acute kidney injury (AKI) and biopsy-proven T cell-mediated rejection (TCMR), adjusting for established risk factors.ResultsAmong 344 recipients (median age 59 years; 62% male), TCMR occurred in 15.7% and AKI in 69.8%. Delta Tac was not associated with TCMR (HR 0.93, 95% CI 0.77 to 1.14) but was associated with higher AKI hazard (HR 1.15 per ng/mL, 95% CI 1.08 to 1.24).DiscussionThese findings suggest that divergence between Hct-adjusted and measured Tac is associated with increased AKI risk without a corresponding signal for rejection.
Heart transplantation outcomes have tremendously improved over the nearly fifty years that the procedure has been performed. As demand continues to grow, there is a persistent shortage of organs. Compounding this is the potential for organs to deteriorate with increasing preservation and transport times. New technologies have been developed to address these issues. These include novel physiologic preservation solutions and preservation devices (which range from those that optimize temperature control to those that use machine perfusion or combinations of these facets) to minimize the risk of ischemic injury. Research is ongoing into these techniques and their potential to improve outcomes by protecting donor organs (particularly in cases of prolonged ischemic times) and expand the donor pool by better preserving grafts from marginal and/or donation after circulatory death donors. There is even research into utilizing these technologies to enable safe cardiac xenograft implantation as well as their role in beating heart transplantation.
The Ajmera Transplant Center and Mayo Clinic hosted the third annual Transplant Artificial Intelligence (AI) Symposium in Toronto, Canada, bringing together expert clinicians, researchers, scientists, and trainees to discuss the current role of AI in transplant medicine. This paper summarizes the third annual Transplant AI Symposium proceedings and talks. Presentations covered a wide range of topics across the transplant continuum, highlighting numerous benefits of AI in transplantation such as organ matching, human-AI collaboration, and survival/risk prediction. Artificial intelligence is most useful when linked to specific clinical problems, especially those involving multimodal or longitudinal data. However, speakers also emphasized ongoing limitations in data quality, generalizability, workflow integration, and fairness. Multiple presentations highlighted the importance of clinician oversight. Overall, the symposium highlighted that the future of transplant AI will depend on careful validation, clinically meaningful implementation, and attention to patient outcomes (Figure 1).
The liver's extraordinary regenerative capacity has fascinated biologists for decades, yet the translation of regenerative biology into clinically effective therapies remains limited. Regeneration is not a simple proliferative response but a tightly orchestrated program initiated by tissue injury and coordinated through inflammatory priming, complement activation, mechanosensory signaling, extracellular matrix remodeling, metabolic reprogramming, and growth factor–driven hepatocyte proliferation. In this review, we synthesize current understanding of the cellular and molecular networks that govern liver regeneration, emphasizing the dynamic crosstalk among hepatocytes, Kupffer cells, liver sinusoidal endothelial cells, hepatic stellate cells, and recruited immune populations. We further examine the major experimental systems used to study regeneration, from classic in vivo hepatectomy models to emerging human-relevant platforms, including organoids, liver-on-a-chip systems, extracellular matrix scaffolds, precision-cut liver slices, and ex vivo perfusion, highlighting both their mechanistic value and translational limitations. We then focus on the growing clinical importance of regeneration in transplantation, where the expanding use of marginal, steatotic, aged, and reduced-size grafts has intensified the need to preserve regenerative competence. In this context, ex vivo machine perfusion offers a uniquely promising platform to study, modulate, and therapeutically prime regenerative pathways before implantation, potentially enabling graft reconditioning strategies that improve outcomes in small-for-size and other high-risk liver grafts.
