Search Results (64)

Kaempferol is a natural flavonol compound widely present in various single-herb remedies and compound formulations used for the treatment of ocular diseases. Despite its inherent pharmaceutical limitations, accumulating evidence indicates that kaempferol exerts broad protective effects against diverse ocular disorders through multiple biological pathways, highlighting its potential as a multi-target therapeutic candidate in ophthalmology. However, current evidence regarding kaempferol-based ophthalmic applications remains fragmented across different ocular diseases and mechanistic investigations, and a comprehensive evaluation of its therapeutic potential, translational challenges, and existing limitations is still lacking. This review systematically summarizes the research progress on kaempferol in the treatment of eye diseases, encompassing its source distribution, structural characteristics, ocular delivery strategies, disease spectrum coverage, molecular mechanisms, and safety profile. By critically evaluating currently available evidence, this review further identifies unresolved issues and translational barriers that hinder the clinical application of kaempferol in ophthalmology. Regarding delivery strategies, carriers such as gelatin nanoparticles, porous bovine serum albumin membranes, platelet-derived extracellular vesicles, and polyvinylpyrrolidone-based nanocomposites have preliminarily improved ocular surface retention and corneal permeability of kaempferol in models of corneal neovascularization and alkali burns. In terms of therapeutic indications, kaempferol has demonstrated protective effects in diverse experimental models, including age-related macular degeneration (AMD), diabetic retinopathy, diabetic cataract, dry eye disease, fungal keratitis, corneal transplant rejection, acute glaucoma, and retinoblastoma. At the mechanistic level, kaempferol exerts comprehensive pharmacological actions—anti-inflammatory, antioxidant, metabolic regulation, anti-angiogenic, and immunomodulatory—by modulating multiple signaling pathways, including MAPK, NF-κB, STAT1/IRF7, Nrf2/HO-1, VEGF/PI3K/Src/Akt/ERK, aldose reductase, estrogen-related receptor alpha (ERRα), and the NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome. Available safety assessments suggest that kaempferol exhibits a generally favorable safety profile across ocular, cellular, systemic, and genetic evaluations. Despite these advances, the clinical translation of kaempferol in ophthalmology remains limited by insufficient clinical and pharmacokinetic evidence, underdeveloped targeted delivery strategies, and a lack of integrated understanding of its molecular basis in ocular protection. By systematically integrating evidence from ocular disease models, molecular mechanisms, delivery strategies, and safety evaluations, this review bridges fragmented knowledge regarding kaempferol-based ophthalmic applications and provides an integrated framework for understanding its therapeutic potential and translational prospects. Overall, this review highlights kaempferol as a promising multi-target therapeutic candidate for ocular diseases and provides insights into its future translational development. Full article

Background: CAV (cardiac allograft vasculopathy) is considered the leading cause of late post-transplant mortality and affects approximately 50% of transplant patients at 10 years post-transplant. Its etiopathogenetic mechanism is considered to be immune-mediated, but the identification of other non-immunological risk factors could represent new therapeutic targets for this pathology. Lipofuscin is due to reactive oxygen species (ROS) and appears to have a determining role in CAV. The aim of this study is to investigate the association between the amount of lipofuscin identified on EMB (endomyocardial biopsy) from patients followed up after heart transplantation, and the presence of CAV detected by coronary angiography. Methods: This retrospective study includes 99 EMBs from 47 transplanted patients, who also had coronary angiography. The amount of lipofuscin, damage to intramyocardial small vessels, vasculitis, Quilty effect, and acute cellular and humoral rejection was evaluated microscopically. Results: 19 CAV cases (19.2%) were identified, of which 15 (68.18% of total CAV cases) were insignificant. Grade 3 lipofuscin affected equally the cases with insignificant and significant CAV, 3 cases (37.5%) from each group. Grade 2 lipofuscin was reported in 10 cases (58.8%) of insignificant CAV, respectively 1 case of significant CAV (5.9%), (p-value of 0.0001). Quantitative evaluation of lipofuscin on microscopic sections revealed 8 EMBs (8.1%) with grade 3 lipofuscin. Two cases (25.0%) with lipofuscin score 3 were associated with moderate ACR (acute cellular rejection), ISHLT 2R and 3 cases (37.5%) with lipofuscin score 3 were associated with mild ACR ISHLT 1R, the differences being statistically significant, (p = 0.0001). Lipofuscin grades 2 and 3 were associated with severe fibrosis in 6 cases (35.3%) and 2 cases (25.0%), respectively (p = 0.042). A statistically significant association between the degree of damage to the intramyocardial small vessels and the amount of intracytoplasmic lipofuscin was observed (p = 0.00014). Discussion: Our study revealed that lipofuscin was more frequently associated with CAV, fibrosis, and damaged small vessels. Oxidative stress influences lipofuscinogenesis and CAV, which leads to endothelial dysfunction and neointimal hyperplasia, which over time will produce progressive narrowing of the vascular lumen and dysfunction of the cardiac allograft. Of the total number of 19 cases with CAV, 17 (89.47%) presented a lipofuscin score of 2 or 3 concomitantly with CAV, (p = 0.0001). This could mean that lipofuscin is not a harmless degradation product. At the same time, the association of a large number of cases with lipofuscin score 2, 10 cases (58.8%) with insignificant CAV could lead to the idea of using lipofuscin as a potential biomarker in the early diagnosis of CAV. Conclusions: We evidenced a significant association between the amount of intracytoplasmic lipofuscin and CAV. Accordingly, lipofuscin might be involved in the pathogenesis of CAV. Further research is needed to clarify the exact mechanisms of this association. Full article

Although the potential role of carbohydrate antigen 125 (CA125) in acute cellular rejection (ACR) has been explored, its role in antibody-mediated rejection (AMR) remains unclear. Since CA125 is associated with inflammation and congestion, we hypothesized that CA125 could reflect key processes in AMR and complement the existing diagnostic methods. We analyzed 491 serum samples from heart transplant recipients undergoing first-year routine endomyocardial biopsies (EMBs). The results of EMB were classified as no-rejection, ACR, or AMR. CA125 levels were measured using a chemiluminescent immunoassay. CA125 concentrations were significantly higher in the AMR group (median 41 [IQR 26–78] U/mL) than in the no-rejection group (median 17 [IQR 11–27] U/mL; p < 0.01), regardless of post-transplantation time. In contrast, no significant differences were observed between the ACR and no-rejection groups (p = 0.124). Receiver operating characteristic analysis demonstrated strong diagnostic performance of CA125 for AMR (area under the curve = 0.821; p < 0.001). CA125 was an independent predictor of AMR (odds ratio, 5.04; p < 0.01). Our results demonstrated that elevated circulating CA125 levels are associated with AMR and exhibit promising diagnostic performance after heart transplantation, highlighting their potential as a non-invasive biomarker. This is further supported by the wide availability, standardization, and reproducibility of CA125 measurements in clinical practice. Full article

Background: Heart transplantation (HT) remains the definitive therapy for end-stage heart failure, yet rejection and cardiac allograft vasculopathy (CAV) continue to limit long-term outcomes. Beyond donor-specific HLA antibodies, non-HLA antibodies, particularly anti-angiotensin II type 1 receptor antibodies (AT1R-Abs), have been implicated in allograft injury, but published findings are heterogeneous. Aim: The aim of this study is to systematically evaluate the evidence linking AT1R gene expression and anti-AT1R antibodies with key post-heart transplant outcomes. Methods: We conducted a systematic review in accordance with PRISMA guidelines. Scopus, PubMed, Web of Science, and the Cochrane Library were searched (December 2025) for cohort and case–control studies evaluating AT1R gene expression and/or AT1R-Ab status in HT recipients and their association with post-transplant outcomes. Two reviewers independently screened studies, extracted data, and assessed risk of bias using the NIH Quality Assessment Tool. Results: Twelve studies encompassing 951 recipients met the inclusion criteria. Five studies evaluated AT1R mRNA expression, reporting variable patterns: several observed reduced AT1R/AT2R transcription after transplantation without clear clinical correlation, whereas others associated higher donor or recipient AT1R expression with transplant coronary artery disease and recurrent rejection. AT1R-Ab prevalence varied widely and appeared to increase after mechanical circulatory support, with substantial seroconversion reported during LVAD support in initially antibody-negative patients. Associations between AT1R-Ab and acute cellular rejection and antibody-mediated rejection were inconsistent across studies, and survival findings were inconclusive; however, some reports linked elevated AT1R-Abs to poorer long-term freedom from adverse events. Evidence regarding CAV was mixed, with signals of increased vasculopathy risk in some cohorts but not others. Conclusions: Current evidence suggests a potential role for AT1R expression and AT1R-Abs in cardiac allograft dysfunction, including rejection phenotypes and vasculopathy. Larger prospective studies with harmonized testing strategies are needed to define clinically meaningful AT1R-Ab cutoffs and clarify their utility in risk stratification and targeted therapeutic trials. Full article

Background: Acute cellular rejection (ACR) remains a significant cause of graft dysfunction after liver transplantation and requires timely detection. Liver biopsy, the diagnostic gold standard for ACR, is invasive and unsuitable for frequent monitoring, while liver enzyme tests lack specificity for detecting ACR. Circulating microRNAs (miRNAs), including miR-122 and miR-885, have been previously identified as predictive biomarkers of ACR in liver transplant recipients. HepatoTrack™ is a serum-based miRNA RT-qPCR assay designed for noninvasive assessment of ACR using these biomarkers. This study evaluated the analytical performance and clinical validity of HepatoTrack™ for diagnosing ACR in liver transplant recipients. Methods: HepatoTrack™ uses 100 μL of serum and a one-step RT-qPCR workflow. It quantifies miR-122 and miR-885 normalized to miR-23a, with synthetic cel-miR-39 included as an exogenous control. Analytical validation assessed performance characteristics. Clinical performance was evaluated in a cohort of liver transplant recipients undergoing for-cause liver biopsy and used for model development and validation. Results: Analytical validation demonstrated robust assay performance. The HepatoTrack™ Prediction Score (HPS) algorithm was trained using 47 subjects from the training cohort based on a linear regression model incorporating longitudinal miRNA changes. In the independent testing cohort (n = 37), HPS achieved a sensitivity of 92.9%, specificity of 73.9%, positive predictive value (PPV) of 68.4%, and negative predictive value (NPV) of 94.4% for biopsy-confirmed ACR. HPS achieved an area under the curve (AUC) of 0.831 compared with 0.731 for ALT and 0.660 for AST. Conclusions: HepatoTrack™ support the analytical and clinical validity for detection of biopsy-confirmed acute cellular rejection in liver transplant recipients. The assay provides a noninvasive molecular test to aid in the diagnosis of acute cellular rejection and may complement existing post-transplant diagnostic evaluation. Full article

Background/Objectives: Cardiac allograft fibrosis is an important limiting factor for long-term graft survival. However, the fibrotic process operating in patients with acute cellular rejection (ACR) remains unclear. We aimed to identify altered serum mRNAs related to cardiac fibrosis in patients with ACR and to evaluate their diagnostic accuracy in detecting rejection episodes. Methods: We included 40 serum samples from recipients of transplants undergoing routine endomyocardial biopsies. Results: Several altered mRNAs associated with fibrosis were detected in patients with ACR. Specifically, the activators of fibroblasts and myofibroblasts (TNS1, FAP and ACTA2), TGF-β signaling (TGFBR1 and JAK1) and WNT signaling (WNT7A and WLS) pathways were significantly different when we compared grade ≥ 2R ACR and/or grade 1R ACR groups with the nonrejection group. Furthermore, TNS1 and WLS presented an area under the curve value > 0.90 for identifying patients with moderate and severe grades of cardiac rejection. Conclusions: In conclusion, we found alterations in the relative abundance of circulating activators of fibroblasts and myofibroblasts, such as FAP or ACTA2, as well as in major profibrotic pathways, including TGF-β and WNT signaling, especially in clinically relevant cardiac rejection. These findings may contribute to improving the surveillance of patients with cardiac transplant and provide new therapeutic strategies for targeting fibrosis process activation. Full article

Background: Acute cellular rejection (ACR) after heart transplantation remains incompletely explained despite standardized immunosuppression. Environmental exposures may contribute to residual immune activation; however, prior studies have focused primarily on air pollution rather than residential land-use composition. Objectives: To determine whether buffer-specific residential environmental composition is associated with rejection risk and whether these associations are scale-dependent and domain-specific. Methods: In this retrospective single-center cohort study, 30 heart transplant recipients contributed 267 biopsy-linked observations. Residential land-use composition was quantified within 300 m, 500 m, 700 m, and 1000 m buffers and aggregated into five domains: trees, other green surroundings, roads, water, and industrial land. Associations with ACR were evaluated using clustered logistic regression models adjusted for time since transplantation. Results: The strongest and only statistically robust associations after FDR correction were observed within the 300 m buffer. Tree-dominant (OR 1.42, 95% CI 1.22–1.65, q = 0.010) and industrial land exposure (OR 1.50, 95% CI 1.28–1.76, q = 0.010) were independently associated with increased odds of ACR. At 500 m, the association with trees persisted nominally (OR 1.39, 95% CI 1.03–1.88, p = 0.034), but did not remain significant after FDR correction, whereas water exposure showed a non-significant trend (OR 1.28, p = 0.057), which did not reach statistical significance. No associations were observed beyond 700 m across all models. Conclusions: Residential environmental composition may be associated with acute cellular rejection after heart transplantation in a scale-dependent manner, with signals confined to the immediate residential environment. Tree-dominant exposure within 300 m showed an association in clustered models; however, this finding was attenuated in mixed-effects sensitivity analyses. These results should be considered exploratory and hypothesis-generating study. Full article

Importance: Immune checkpoint inhibitors (ICIs) have expanded downstaging options for hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), enabling bridging to liver transplantation (LT). However, the immunologic consequences of pre-transplant checkpoint blockade, particularly the risk of allograft rejection mediated by persistent T-cell activation, remain insufficiently characterized, creating a critical knowledge gap at the intersection of immuno-oncology and transplant medicine. Objective: To synthesize current evidence on oncologic outcomes, rejection risk, washout intervals, donor-type considerations, and immunosuppression strategies in LT recipients with pre-transplant ICI exposure. Evidence Review: A PRISMA-ScR-guided review was conducted using MEDLINE, Embase, Cochrane Library, and Web of Science from January 2015 through December 2025. Studies reporting outcomes in adult LT recipients with documented pre-transplant ICI exposure for HCC or CCA were included. Methodological quality was descriptively assessed using the Newcastle-Ottawa Scale and JBI tools. Given study heterogeneity, findings were narratively synthesized. Findings: Thirty studies were included. In HCC, neoadjuvant ICI therapy achieved downstaging to Milan criteria in 75.6% of candidates in the largest multicenter cohort (n = 117), with complete pathologic response rates ranging from 23.8% to 40%. Rejection rates ranged from 16.3% to 20.2% in large series but increased to 56.3% with short washout intervals. Washout intervals exceeding 50 days were associated with rejection rates approaching non-ICI controls, while an individual patient meta-analysis of 91 patients estimated each additional week of washout was associated with approximately 8% reduction in rejection risk, suggesting that approximately 94 days may be required to achieve a rejection probability of 20% or less. Rejection occurred at a median of 7–10 days post-transplantation, earlier than typical acute cellular rejection. Three-year overall survival exceeded 85.3% in major cohorts. Donor type was not consistently associated with rejection after adjustment for washout duration. CCA data remain limited. Immune-related adverse events during ICI therapy were associated with increased post-transplant rejection risk. Conclusions: Pre-transplant ICI therapy may expand transplant eligibility in advanced hepatobiliary malignancies but carries time-dependent rejection risk. Current evidence supports a minimum washout interval of at least 50 days, with emerging data favoring 90–94 days when feasible. Prospective multicenter studies, biomarker-guided risk stratification, and standardized immunosuppression protocols are needed to refine patient selection and optimize timing. Full article

Background: Renal allograft rejection remains a major challenge in transplantation. Current diagnostic approaches, including biopsies, are invasive and may fail to detect subclinical immune activation, potentially contributing to progressive graft dysfunction. Reliable, non-invasive biomarkers capable of monitoring immune activation and distinguishing rejection phenotypes are therefore needed. Methods: In this retrospective study, we evaluated serum neopterin as a biomarker of immune activation and graft status over 12 months following transplantation. Associations between neopterin levels and immune parameters, including natural killer (NK)-to-CD3⁺CD16/CD56⁺ T cell ratios, cytokines (IFN-γ and IL-10), and CD4⁺CD25⁺FoxP3⁺ T cell frequencies, were assessed. A total of 211 first renal allograft recipients were followed longitudinally, including patients with acute rejection (AR) and matched stable graft (SG) recipients. Serum neopterin was quantified by enzyme immunoassay, and immunophenotyping, mRNA expression, and cytokine profiling were performed on peripheral blood samples. Results: Serum neopterin levels were significantly elevated in AR compared to SG recipients, with a threshold of 57 nmol/L distinguishing AR with 81% sensitivity and 80% specificity. While IFN-γ demonstrated higher diagnostic performance in cross-sectional analysis, neopterin showed a more sustained elevation over time, remaining increased in AR recipients even at later post-transplant time points. Neopterin correlated positively with IFN-γ, but not IL-10, and inversely with CD4⁺CD25⁺FoxP3⁺ T cell frequency. NK cells were enriched during rejection, whereas CD3⁺CD16/CD56⁺ T cells were more prominent in graft stability. The NK-to-CD3⁺CD16/CD56⁺ T cell ratio was highest during acute cellular rejection. Conclusions: Neopterin reflects Th1-associated immune activation in renal allograft recipients and provides a temporally stable, non-invasive marker of immune status. Although it does not outperform IFN-γ levels at the time of rejection, its stability and sustained elevation suggest a complementary role in longitudinal monitoring. Integration of neopterin with immune parameters, including cytokine profiles and cellular subsets, may enhance the assessment of graft immunological status and support clinical decision-making. Full article

Background: Heart transplantation remains the definitive therapy for selected patients with end-stage heart failure, but outcomes are limited by acute rejection, chronic allograft injury, and cardiac allograft vasculopathy. Endomyocardial biopsy (EMB) remains the reference standard for rejection surveillance but is invasive and imperfectly captures diffuse myocardial injury. Cardiovascular magnetic resonance (CMR) offers noninvasive, multiparametric assessment of graft structure, function, tissue composition, and perfusion. We aimed to review current evidence supporting CMR in post-heart transplant surveillance and to evaluate the performance of serial CMR for acute cellular rejection in a prospective cohort. Methods: We performed a focused narrative review of the literature on CMR for detection of acute rejection, assessment of chronic allograft injury and prognosis, and evaluation of cardiac allograft vasculopathy and microvascular disease. In parallel, we conducted a prospective observational study of adult heart transplant recipients undergoing early post-transplant CMR (CMR1) and follow-up CMR (CMR2) with temporally matched EMB. Multiparametric CMR included cine imaging, native T1 and T2 mapping, extracellular volume fraction (ECV), and late gadolinium enhancement (LGE). Clinically significant acute cellular rejection was defined as ISHLT grade ≥ 2R. Results: Eighteen recipients were included (median 53 days to CMR1 and 192 days to CMR2). Baseline CMR parameters correlated with invasive hemodynamic and biomarkers. Two patients had biopsy-proven ≥2R rejection at follow-up. T2 values at CMR2 were significantly higher in rejection versus non-rejection patients (59.0 ± 1.4 ms vs. 51.1 ± 1.9 ms; p = 0.015), with greater LGE burden in rejection (p = 0.029). In longitudinal analyses, rejection was associated with divergent patterns of cardiac remodelling and tissue characterization, including increases in indexed ventricular volumes and T2 over time, whereas non-rejection patients demonstrated stable ventricular volumes and a decline in T2. Conclusions: Multiparametric CMR, anchored by T2 mapping, provides clinically meaningful, non-invasive information for acute rejection surveillance after heart transplantation and complements EMB within a personalized, risk-adapted follow-up framework. Establishing individualized baseline CMR phenotypes and monitoring longitudinal changes may support more personalized, less invasive graft surveillance strategies. Larger multicentre prospective studies are needed to define standardized implementation pathways. Full article

Background/Objectives: To evaluate the outcome of developing BKPyV-DNAemia and presumptive BKPyV-nephropathy (BKPyV-DNAemia ≥ 10⁴ copies/mL for more than 2 weeks) within the first 2 years post-transplant in a Belgian population of renal transplanted children. Methods: All children transplanted between 1 January 2010 and 31 December 2022 at Queen Fabiola Children’s University Hospital, Brussels (HUDERF) and at University Hospitals Leuven (UHL) were included in this retrospective study and 86 were followed for at least 2 years post-transplantation. Results: Within the first 2 years, 11/86 (13%) patients developed BKPyV-DNAemia ≥ 10⁴ copies/mL (82% within the first 6 months). Among the 11 patients, 7 underwent a biopsy, of whom 4 were confirmed to have biopsy-proven BKPyV-nephropathy. Of those 11 patients, 4 (36%) developed an acute cellular rejection following immunosuppression reduction. The median eGFR at 2 years post-transplantation was 69 mL/min/1.73 m² (IQR: 59–79) in the seven patients with presumptive BKPyV-nephropathy and 40 mL/min/1.73 m² (IQR: 39–41) in the four with biopsy-proven BKPyV-nephropathy. At last follow-up visit, the median eGFR was 65 mL/min/1.73 m² (IQR: 59–71) in the children with presumptive BKPyV-nephropathy, and 28 mL/min/1.73 m² (IQR: 20–34) in the patients with biopsy-proven BKPyV-nephropathy. No risk factors for developing BKPyV-DNAemia were identified. Conclusions: Our study confirms that while BKPyV-DNAemia monitoring is essential in pediatric kidney transplant recipients, decisions based solely on viral load risk overtreatment and immunological complications. A personalized approach integrating viral, clinical, and immunological markers is urgently needed to balance infection control with graft preservation. Full article

Background: Alemtuzumab is a recombinant DNA-derived humanized monoclonal antibody directed against the 21–28 kd cell surface glycoprotein, CD52. Alemtuzumab is used as an organ anti-rejection therapy in transplant recipients. Neuro-ophthalmic adverse effects are rarely described, and, to our knowledge, accommodative spasm has not previously been reported in a transplant recipient. Case Description: A thirty-nine-year-old woman with genetically confirmed NPHP1-associated nephronophthisis, with stage F3 fibrosis, developed persistent bilateral blurred vision 72 h following alemtuzumab administration for a biopsy-proven acute cellular rejection, approximately six to seven weeks post-transplant. Initial attribution to hyperglycaemia and tacrolimus toxicity delayed recognition. Cycloplegic refraction confirmed a marked hyperopic shift (+2.75 D right eye, +2.50 D left eye) with significant improvement in visual acuity, consistent with accommodative spasm. Systemic evaluations excluded hyperglycaemia-related lens changes, calcineurin inhibitor neurotoxicity, and cytomegalovirus retinitis. MRI was not pursued in the absence of red flag neurological features, and because a definitive ophthalmic diagnosis had been made. Management and Outcome: The patient was managed expectantly, as cycloplegic refraction had already confirmed the diagnosis, and symptoms were improving. Therapeutic cycloplegia (e.g., atropine) was withheld to avoid impairing near vision and driving ability. Full resolution occurred within 4 to 6 weeks without intervention. Drug exposure to onset of symptoms was 72 h; onset of symptoms to diagnostic confirmation was 22 days; total symptom duration was 5.5 weeks, and recovery was 2 weeks after diagnosis. Conclusions: This case represents the first reported transplant case of alemtuzumab-associated accommodative spasm. Causality assessment supports a WHO-UMC classification of “Probable”, aligning with five Bradford–Hill considerations (temporality, biological plausibility, consistency, specificity, and analogy), but without statistical “strength of association” given that this is a single case report. Early cycloplegic refraction should be incorporated into the evaluation of post-alemtuzumab visual complaints, and clinicians should contribute to pharmacovigilance through structured reporting to capture these rare but important events. Full article

Vascularised composite allotransplantation (VCA) has an evolving role in the reconstruction of complex functional and aesthetic deficits non-amenable to autologous or implant-based reconstructive modalities. International applications of VCA span upper extremity, face, abdominal wall, uterus, and penile transplantation, with more than 300 procedures performed worldwide. Among these, abdominal wall transplantation has uniquely contributed to the development of the sentinel skin flap (SSF) concept, in which solid organ transplant patients undergo simultaneous transplantation of a solid organ and a donor-derived vascularised skin flap, with the skin component of the SSF being trialled internationally as a means of monitoring for rejection within the solid organ allograft. Despite growing clinical success, VCA continues to face substantial barriers to wider adoption. Acute rejection remains highly prevalent, affecting up to 89% of recipients, with significant morbidity linked to intensive systemic immunosuppression. Challenges are further amplified by the unique immunological heterogeneity of composite grafts, ethical concerns surrounding identity-linked tissues, and the lack of standardised outcomes reporting across VCA subtypes. Advances in machine perfusion technologies and emerging cellular and biomaterial-based immunomodulation strategies show promise in reducing immunosuppression burden and improving graft longevity. This review outlines the current state of VCA, including clinical applications, outcomes, and mechanistic insights from pre-clinical studies, while highlighting key ethical considerations and evolving regulatory frameworks. Future progress will depend on standardised reporting systems, improved donor–recipient matching, better understanding of ischemia–reperfusion injury, and the development of next-generation immunosuppressive/immuno-modulatory therapies. Collectively, these innovations position VCA as a rapidly advancing field with significant potential to redefine reconstructive and transplant surgery. Full article

Cardiac allograft rejection remains a major cause of graft dysfunction post-transplant. While histology is the current diagnostic standard, it may miss early immune and inflammatory events. This study evaluated the immunohistochemical expression of matrix metalloproteinases 2 (MMP2), 9 (MMP9), and interleukin-1 beta (IL-1β) in cardiac transplant patients, correlating their expression with acute cellular rejection (ACR), antibody-mediated rejection (AMR), inflammation, vasculitis, the Quilty effect, and immune markers. Fifty-nine endomyocardial biopsy specimens were retrospectively analyzed. Immunohistochemical staining for MMP2, MMP9, and IL-1β was assessed based on nuclear, cytoplasmic, and membranous expression. Correlations were evaluated using Fisher’s exact test and odds ratios (ORs) with 95% confidence intervals (CIs). IL-1β nuclear expression showed strong associations with ACR (p = 0.0001), inflammation, vasculitis, and immune/endothelial markers (all p < 0.003). Nuclear MMP9 expression correlated with ACR and immune cell markers and was borderline significant for AMR (p ≈ 0.05). Cytoplasmic MMP2 (>50%) was significantly associated with AMR (OR = 7.47, p = 0.0002). No marker correlated with the Quilty effect. The immunohistochemical profiles of IL-1β and MMP9 support their involvement in immune-mediated injury in cardiac allograft rejection, with IL-1β emerging as a sensitive marker of early inflammation. MMP2 appears to be more relevant to humoral rejection processes. These findings suggest that selected tissue biomarkers may enhance diagnostic precision and support early detection of graft injury when integrated with conventional histology. Full article

Background and Objectives: Cardiac transplantation is currently the elective treatment choice in end-stage heart failure, and cellular rejection is a predictive factor for morbidity and mortality after surgery. We proposed an evaluation of the clinicopathologic factors involved in the mechanism of rejection. Materials and Methods: This study included 146 patients who underwent transplantation at the Institute of Cardiovascular Diseases and Transplantation in Targu Mures between 2010 and 2023, and we evaluated the function and structure of the myocardium after surgery by using endomyocardial biopsy. Results: Overall, 120 men and 26 women underwent transplantation, with an approximately equal proportion under and over 40 years old (48.6% and 51.4%). Evaluating the degree of acute cellular rejection according to the International Society for Heart and Lung Transplantation classification showed that most of the patients presented with acute cellular rejection (ACR) and antibody-mediated rejection (AMR) grade 0, and most cases of ACR and AMR were reported with mild changes (13% or 10.3% patients). Therefore, the most frequent histopathologic diagnoses were similar to lesions unrelated to rejection (45.2% of patients) and ischemia–reperfusion lesions (25.3% patients), respectively. Conclusions: Although 82.2% of the transplanted cases showed no rejection (ISHLT score 0), non-rejection-related lesion-like changes were present in 45.2% of cases, and because more of the non-rejection-related criteria could be detected, it may be necessary to adjust the grading of the rejection criteria. The histopathologic changes that characterize rejection are primarily represented by the mononuclear inflammatory infiltrate; in our study, inflammatory changes were mostly mild (71.9%), with myocyte involvement in all cases. These changes are associated with and contribute to the maintenance of the rejection phenomenon. Full article