Search Results (596)

Antibody-mediated rejection is a critical factor in acute and chronic allograft rejection, with Human Leukocyte Antigen as the primary target of the humoral immune response in kidney transplants. In addition to HLA antibodies, non-HLA Abs also play a significant role in AMR. These non-HLA Abs, which can target either autoantigens or alloantigens, may be present pre-transplantation or develop post-transplant. They are associated with various types of allograft injury. The major non-HLA Abs include those directed against the angiotensin II type 1 receptor, endothelin type A receptor, and MICA, as well as other antigens such as vimentin, collagens, and anti-endothelial cell antibodies. Factors such as ischemia, reperfusion injury, and calcineurin inhibitor toxicity can trigger the pathogenic activity of these Abs. The mechanisms underlying non-HLA Ab production are not yet fully understood but are thought to involve endothelial injury and the exposure of neoantigens. Research indicates that these non-HLA Abs can cause graft injury through both complement-dependent and complement-independent pathways. However, detecting non-HLA Abs remains a challenge due to the lack of reliable diagnostic tools. Current treatment strategies for managing the effects of pathogenic non-HLA Abs include intravenous immunoglobulin, plasmapheresis, rituximab, and bortezomib. Early identification of high-risk patients and timely intervention are crucial to preventing graft failure. This review examines the development, mechanisms, and clinical significance of non-HLA Abs in kidney transplantation, highlighting the need for improved diagnostic methods and tailored therapeutic approaches. Full article

Background/Objectives: New monitoring methods are being developed to improve the kidney transplant outcome. Among them, the measurement of Torque Teno virus load (TTV load) has been associated with the overall immunosuppressive status and the percentage of donor-derived circulating free DNA (dd-cfDNA) with molecular graft injury, mainly related to antibody-mediated rejection (AbMR). Both methods provide complementary information, but they have not been previously used together for the monitoring of kidney transplant recipients (KTx). Methods: A prospective study including 42 KTx performed in our centre was conducted, in which we monitored dd-cfDNA using a targeted NGS assay (AlloSeq cfDNA) in the first month and the TTV load with in-house PCR in the first and third months. Results: Eleven KTx with high molecular injury defined by dd-cfDNA ≥ 1.0% were selected. The TTV load showed a non-significant trend of being lower in AbMR patients (2.91, IQR 4.18 vs. 3.48, IQR 1.47 log10 copies/mL, p = 0.788). No overimmunosuppressed patient developed AbMR, whereas 40% of non-overimmunosuppressed patients showed AbMR (p = 0.428). The TTV load increased more in the AbMR-treated KTx (0.00, IQR 4.71 vs. +6.58, IQR 4.04 log10 copies/mL, p = 0.042) from months one to three, with all AbMR-treated KTx becoming overimmunosuppressed. KTx with opportunistic infections showed higher TTV loads in the third month (5.18, IQR 5.92 vs. 11.53, IQR 3.54 log10 copies/mL, p = 0.024). Conclusions: KTx with molecular injury secondary to rejection tended to be less immunosuppressed, as indicated by a low TTV load. After AbMR therapy, all KTx became overimmunosuppressed and suffered a higher risk of opportunistic infections. Dual monitoring provides useful complementary information for the follow-up of kidney transplant recipients. Full article

Background/Objectives: Donor-derived cell-free DNA (dd-cfDNA) is a marker of graft injury that increases in acute rejection and has excellent negative predictive value. Left ventricular global longitudinal strain (LVGLS) and strain-derived myocardial work indices are novel echocardiographic parameters with growing applications. Still, they have been poorly investigated in heart transplant (HTx) recipients so far. We sought to examine the diagnostic impact of left ventricular longitudinal strain-derived indices in diagnosing myocardial injury as assessed by dd-cfDNA after HTx. Methods: Since October 2022, HTx recipients have been shifted from our endomyocardial biopsy (EMB)-based rejection surveillance protocol to a monthly dd-cfDNA-led rejection assessment. We analysed the percentage of donor-derived to total cell-free DNA. For echocardiographic analysis, patient selection was restricted to those transplanted ≥ 6 months. We used 2D speckle-tracking echocardiography to assess LVGLS and strain-derived myocardial work parameters. Results: We analysed four hundred and forty-nine dd-cfDNA samples from seventy-one patients until November 2024. The mean dd-cfDNA fraction remained very low (0.13 ± 0.06%). Eighty-eight percent of surveillance EMBs that would have otherwise been performed were avoided. The mean LVGLS was lower than the literature reference values. We found no correlation between dd-cfDNA and LVGLS. Transplanted hearts had different myocardial work indices than the reference values reported in the literature. Conclusions: dd-cfDNA effectively rules out clinically significant acute rejection and decreases the need for invasive surveillance EMBs. LVGLS seems less sensitive than dd-cfDNA for the identification of myocardial injury in the early stages of HTx rejection in patients at low risk for rejection. Full article

Background/Objectives: Ischemic time plays a crucial role in graft function and survival during kidney transplantation. Cooling methods, including cold perfusion and ice slush, are predominantly applied to preserve the kidney, but they may cause uneven cooling and complications. The Organ Pocket^®, an insulated gel bag, has been introduced as an alternative cooling method. However, no studies have compared renal temperature changes between the Organ Pocket^® and conventional cooling methods. Methods: We retrospectively analyzed 49 cases of living-donor kidney transplantation. Among these, 33 received kidney grafts preserved with the Organ Pocket^® (OP group), and 16 underwent conventional cooling (control group). Renal surface temperatures were recorded at 5 min intervals during vascular anastomosis using thermography. Postoperative renal function was assessed with estimated glomerular filtration rate (eGFR), serum creatinine (sCr), and liver-type fatty acid-binding protein (L-FABP) levels. Results: The OP group demonstrated significantly higher renal surface temperatures than the control group during vascular anastomosis (p < 0.05). Renal surface temperature before reperfusion was 20.4 °C ± 2.5 °C and 17.2 °C ± 2.5 °C in the OP and control groups, respectively. No significant differences in postoperative eGFR, sCr, and L-FABP levels; delayed graft function (DGF); or acute rejection rates were observed between the groups. Conclusions: The Organ Pocket^® effectively stabilized renal temperatures during vascular anastomosis without direct cooling, thereby reducing continuous manual cooling requirements. Short-term renal function outcomes were comparable between groups; however, the Organ Pocket^® may improve surgical efficiency and be particularly beneficial in robot-assisted kidney transplantation. Further studies are warranted to investigate its long-term benefits. Full article

Background: Breast reconstruction (BR) following mastectomy plays a critical role in restoring breast contour and improving patients’ quality of life. Acellular dermal matrices (ADMs) have emerged as valuable adjuncts in BR, providing structural support and enhancing soft tissue integration. However, their radiological characteristics remain underexplored, leading to potential misinterpretation and diagnostic challenges. This study aims to evaluate the imaging features of ADM in post-mastectomy patients using conventional imaging modalities, identifying its temporal evolution and clinical implications for radiologists and surgeons. Materials and Methods: This single-centre retrospective study included breast cancer patients who underwent mastectomy followed by ADM-assisted BR. Patients were monitored using standardised radiological follow-up protocols, including digital mammography (DM) and ultrasound (US), at 6 (T0), 12 (T1), and 18 months (T2) postoperatively. The primary outcomes assessed were the presence and evolution of ADM-related imaging findings, differentiation between normal ADM integration and pathological changes, and the role of different imaging modalities in ADM evaluation. Results: Sixty-three patients met the inclusion criteria and underwent radiological follow-up. At T0, ADM was identified in 16% of cases, primarily as a peri-capsular hypoechoic thickening on US and a linear peri-implant density on DM. At T1, these findings were partially resolved, with 11% of cases still displaying peri-capsular changes. By T2, imaging signs of ADM were further reduced, with only 7% of cases showing residual peri-capsular thickening or pseudonodular formations. No ADM-related complications, graft rejection, or implant loss were detected. These findings suggest a progressive integration of ADM into the host tissue over time, with characteristic imaging changes that must be recognised to avoid misdiagnosis or unnecessary interventions. Conclusions: ADM exhibits a dynamic radiological evolution in post-mastectomy BR, with its imaging characteristics gradually fading. Recognising these features is critical for radiologists and surgeons to ensure accurate interpretation and optimised patient management. A structured imaging follow-up protocol, incorporating US as the primary modality and MRI in cases of inconclusive findings, is recommended to improve diagnostic accuracy. Future multicentre studies with extended follow-up and advanced imaging techniques are necessary to refine radiological criteria and further explore ADM integration patterns. A multidisciplinary approach is essential to enhance clinical decision-making, reduce unnecessary interventions, and optimise patient outcomes in ADM-assisted BR. Full article

Kidney transplantation remains the gold standard for managing end-stage kidney disease, providing superior survival and quality-of-life outcomes compared to dialysis. Despite the ongoing gap between organ availability and demand, it is inevitable that kidney transplantation will continue to grow. This is owed to broader organ sharing, increased comfort of transplant programs with marginal kidney utilization, and the expansion of paired exchange among living donor kidneys. The evolution of kidney transplantation could not have been possible without the availability of effective immunosuppressive regimens that prevent rejection and maintain graft function. Mycophenolic acid and calcineurin inhibitors continue to serve as the foundation of modern maintenance immunosuppression. While these agents have markedly reduced acute rejection rates, their long-term efficacy in graft survival remains suboptimal. Alternative immunosuppressive therapies, including belatacept and mammalian target of rapamycin inhibitors, have demonstrated potential benefits. However, concerns regarding an increased risk of rejection have limited their widespread adoption as primary treatment options. In addition to ongoing efforts to refine steroid- and calcineurin inhibitor-sparing strategies, the identification of practical and quantifiable biomarkers for predicting long-term graft survival remains a critical objective. This review evaluates contemporary immunosuppressive protocols, highlights existing challenges, and explores future directions for optimizing long-term transplant outcomes. Full article

Background and Objectives: The aim of this study was to investigate the changes in the SIRT family, the effects of sirtuins on kidney graft function, and their potential as biomarkers in patients who develop rejection after kidney transplantation. Materials and Methods: Blood samples were collected from 45 kidney transplant patients before and after rejection. Some of these patients experienced T-cell-mediated early rejection (TCMR), while others presented antibody-mediated late rejection (ABMR). The mRNA expression levels of SIRT-1, SIRT-3, and SIRT-7 were measured via real-time PCR, while the protein levels of SIRT-1, SIRT-2, SIRT-3, SIRT-5, and SIRT-7 were assessed using ELISA. Patients were grouped based on rejection type and histological characteristics. Statistical analyses were performed using SPSS software (V23). Results: The mean age of the patient group was 42.22, while the control group had a mean age of 35.23 (p = 0.002). SIRT-1, SIRT-3, and SIRT-7 levels were significantly higher in patients with rejection (p < 0.001). In patients with late-stage rejection, SIRT-3 was found to be associated with interstitial fibrosis and C4d accumulation. SIRT-7 levels showed a weak correlation with potassium levels (p = 0.014). Conclusions: Our findings demonstrate significant changes in the SIRT family during both early- and late-stage rejection processes. Particularly, the role of SIRT-3 in the late stage is highlighted, suggesting the potential use of this gene as a biomarker for managing rejection processes. These findings could provide valuable insights for developing treatment strategies in organ transplantation. Full article

The large-scale application of aromatic polyamide (PA) thin-film composite (TFC) membranes for reverse osmosis has provided an effective way to address worldwide water scarcity. However, the water permeability and salt rejection capabilities of the PA membrane remain limited. In this work, cyclic micropores based on crown ether were introduced into the PA layer using a layer-by-layer interfacial polymerization (LbL-IP) method. After interfacial polymerization between m-phenylenediamine (MPD) and trimesoyl chloride (TMC), the di(aminobenzo)-18-crown-6 (DAB18C6) solution in methanol was poured on the membrane to react with the residual TMC. The cyclic micropores of DAB18C6 provided the membrane with rapid water transport channels and improved ion rejection due to its hydrophilicity and size sieving effect. The membranes were characterized by FTIR, XPS, SEM, and AFM. Compared to unmodified membranes, the water contact angle decreased from 54.1° to 31.6° indicating better hydrophilicity. Moreover, the crown ether-modified membrane exhibited both higher permeability and enhanced rejection performance. The permeability of the crown ether-modified membrane was more than ten times higher than unmodified membranes with a rejection above 95% for Na₂SO₄, MgSO₄, MgCl_2, and NaCl solution. These results highlight the potential of this straightforward surface grafting strategy and the modified membranes for advanced water treatment technologies, particularly in addressing seawater desalination challenges. Full article

Background: Kidney transplantation (KTx) is a safe procedure that improves the life expectancy and quality of life of patients requiring it. However, despite the known benefits for patients who receive a kidney transplant, non-adherence to immunosuppressive medication is an unsolved problem, reflected mainly by graft rejection. Objective: The aim of this study is to systematically review the existing literature on adherence factors to medication after renal transplantation. Methods: A systematic literature review of studies published since 2010 was conducted in three databases. Records for the search were limited to publications from 2010 to 2024, available in full-text. The search was carried out in July 2024. In total, 2632 abstracts were downloaded from the different databases. Inclusion criteria were papers of any type (quantitative or qualitative) whose objective was the identification of predictors of adherence for patients who were prescribed immunosuppressive medication after kidney transplantation. Results: The predictors of adherence to treatment found in the systematic review were grouped into the following categories of the World Health Organization classification: socio-economic factors, factors related to the treatment/therapy, patient-related factors, disease-related factors, and health care system factors. Most of the studies were excluded, and in the end, 30 were included in the final analysis. According to these studies, a set of strong predictors was identified, but discrepancies among the variables of gender in young patients, pre-emptive transplantation, and the time of the transplantation were detected. Conclusions: In this study, we identified specific predictors and directions for the association of those predictors with adherence to immunosuppressive medication for patients after KTx. Further research should consider conducting reviews for different patient sub-groups on medication adherence and the development and validation of a screening instrument for adherence/non-adherence factors that clinicians could use as a detection tool for subjects at risk of low adherence. Full article

Kidney transplantation is currently the treatment of choice for patients with end-stage kidney diseases. Although significant advancements in kidney transplantation have been achieved over the past decades, the host’s immune response remains the primary challenge, often leading to potential graft rejection. Effective management of the immune response is essential to ensure the long-term success of kidney transplantation. To address this issue, immunosuppressives have been developed and are now fully integrated into the clinical management of transplant recipients. However, the considerable inter- and intra-patient variability in pharmacokinetics (PK) and pharmacodynamics (PD) of these drugs represents the primary cause of graft rejection. This variability is primarily attributed to the polymorphic nature (genetic heterogeneity) of genes encoding xenobiotic-metabolizing enzymes, transport proteins, and, in some cases, drug targets. These genetic differences can influence drug metabolism and distribution, leading to either toxicity or reduced efficacy. The main objective of the present review is to report an historical overview of the pharmacogenetics of immunosuppressants, shedding light on the most recent findings and also suggesting how relevant is the research and investment in developing validated NGS-based commercial panels for pharmacogenetic profiling in kidney transplant recipients. These advancements will enable the implementation of precision medicine, optimizing immunosuppressive therapies to improve graft survival and kidney transplanted patient outcomes. Full article

Liver transplantation is a critical and evolving field in modern medicine, offering life-saving treatment for patients with end-stage liver disease and other hepatic conditions. Despite its transformative potential, transplantation faces persistent challenges, including a global organ shortage, increasing liver disease prevalence, and significant waitlist mortality rates. Current donor evaluation practices often discard potentially viable livers, underscoring the need for refined graft assessment tools. This review explores advancements in graft evaluation and utilization aimed at expanding the donor pool and optimizing outcomes. Emerging technologies, such as imaging techniques, dynamic functional tests, and biomarkers, are increasingly critical for donor assessment, especially for marginal grafts. Machine learning and artificial intelligence, exemplified by tools like LiverColor, promise to revolutionize donor-recipient matching and liver viability predictions, while bioengineered liver grafts offer a future solution to the organ shortage. Advances in perfusion techniques are improving graft preservation and function, particularly for donation after circulatory death (DCD) grafts. While challenges remain—such as graft rejection, ischemia-reperfusion injury, and recurrence of liver disease—technological and procedural advancements are driving significant improvements in graft allocation, preservation, and post-transplant outcomes. This review highlights the transformative potential of integrating modern technologies and multidisciplinary approaches to expand the donor pool and improve equity and survival rates in liver transplantation. Full article

The Human Leukocyte Antigen (HLA) system forms the central part of the immune system and is crucial in the recognition and elimination of “non-self” antigens. While this role of the HLA system is essential in the effective defense of the organism against pathogens, it is undesirable in organ and tissue transplantation because it enables the recognition of mismatched HLA molecules of the donor as being foreign and stimulates the graft rejection reaction. Organ transplantation involves the introduction of antigens that are more or less mismatched to the recipient; therefore, in order to achieve the best possible match in the HLA system between the recipient and the donor, a whole series of immunogenetic tests is performed, including crossmatching (XM). If performed before kidney transplantation, it represents the final in vitro test to rule out the presence of donor-specific antibodies, which may cause graft rejection and which may not have been detected by earlier serum screening. The beginning of XM was marked by the complement-dependent cytotoxicity (CDC) method developed by Terasaki and colleagues in 1964. Later, as a result of advances in technology and the need for methods that overcome the limitations of CDC, flow cytometry and Luminex XM assays were developed. The introduction of solid-phase technology brought a new dimension to the detection of low-level HLA antibodies and the determination of their specificities, which enabled the development and implementation of the virtual XM test (vXM). It is an in silico test that assesses the immunological match between the recipient and the organ donor based on the analysis of the specificity of the antibodies present in the recipient’s serum and the HLA typing of the organ donor. Each method has its own advantages and limitations, which are described below and need to be taken into account, considering their significant impact on clinical application in kidney transplantation. Full article

Objectives: Tacrolimus, a Biopharmaceutics Classification System (BCS) class II drug, is widely used for transplant patients to prevent graft rejection. To enhance its bioavailability, amorphous solid dispersion (ASD) formulations were developed and evaluated. The release properties of several ASD-based tacrolimus formulations were studied using an in-house USP IV dissolution method. Methods: The pharmacokinetics of a promising test product were compared with the commercially available Advagraf^® in a pilot clinical bioequivalence study with 12 healthy subjects. A previously published PBPK model for tacrolimus was validated using in vivo data and then applied to predict the human pharmacokinetics of several ASD-based tacrolimus formulations. Results: This study compares the pharmacokinetic (PK) parameters—AUC, Cmax, and Tmax—of Advagraf^® and a test formulation using two methodologies: one incorporating the dissolution profile directly into the PBPK model and the other utilizing the DLM approach. The results show that both methods provided accurate predictions for Cmax and Tmax, with the dissolution profile approach underestimating AUC slightly, while the DLM method predicted AUC adequately. Sensitivity analysis refining the DLM scalars in the Ileum and Colon led to optimized predictions of PK parameters. Furthermore, this study explores the use of PBPK modeling to predict in vivo behavior for additional tacrolimus formulations, highlighting the influence of formulation composition, such as the inclusion of Eudragit-S100, on dissolution profiles and bioavailability. Conclusions: This study evaluates formulations with different compositions and manufacturing characteristics; key factors that could influence their performance in the body were identified. These insights—spanning qualitative, quantitative, and manufacturing aspects—can greatly simplify the development of generic drugs, offering strong evidence of the critical role that physiologically based pharmacokinetic (PBPK) modeling can play in the early phases of generic drug development, especially in designing and assessing biopredictive dissolution methods. Full article

Millions of people request bone regeneration every year, and the market for bone grafting materials has a positive trend. The most used biomaterials applied to replace and regenerate bone are based on collagen and different types of ceramics in order to mimic natural bone matrix. However, there are a lot of implant-associated infections after surgery, or the implants are rejected because of reduced biocompatibility, and this is why the research into graft bone materials is still a challenge. This study aims to develop and characterize novel biomimetic bone fillers which have simultaneously both antimicrobial properties and biocompatibility with human bone marrow—derived mesenchymal stem cells (BMSCs). Type I collagen and calcium triphosphate in a ratio of 1:1 were used as a control, according to our previous studies, and ZnO, functionalized with different percentages of Satureja thymbra L. essential oils, was added as an antimicrobial, promoting bone growth, mineralization, and formation. The bone fillers were obtained by freeze-drying in spongious forms and characterized by Fourier Transform Infrared Spectroscopy (FT-IR), Scanning Electron Microscopy (SEM), water uptake, biodegradability over time, antimicrobial activity against Staphylococcus aureus and Escherichia coli and viability and proliferation of human BMSCs. The graft material showed a higher porosity with interconnected pores, gradual resorption over time and a balance between antimicrobial properties and biocompatibility and was chosen as an ideal bone filler. Full article

Background/Objectives: Human pancreatic islet transplantation shows promise for long-term glycemic control in diabetes patients. A shortage of healthy donors and the need for continuous immunosuppressive therapy complicates this. Enhancing our understanding of the immune tolerance mechanisms related to graft rejection is crucial to generate safer transplantation strategies. This review will examine advancements in immune protection strategies for stem cell-derived islet therapy and discuss key clinical trials involving stem cell-derived β-cells and their protective strategies against the host immune system. Methods: A comprehensive literature search was performed on peer-reviewed publications on Google Scholar, Pubmed, and Scopus up to September 2024 to extract relevant studies on the various strategies of immune evasion of stem cell-derived β-cells in humans. The literature search was extended to assimilate all relevant clinical studies wherein stem cell-derived β-cells are transplanted to treat diabetes. Results: Our analysis highlighted the importance of human pluripotent stem cells (hPSCs) as a potentially unlimited source of insulin-producing β-cells. These cells can be transplanted as an effective source of insulin in diabetes patients if they can be protected against the host immune system. Various strategies of immune protection, such as encapsulation and genetic manipulation, are currently being studied and clinically tested. Conclusions: Investigating immune tolerance in hPSC-derived islets may help achieve a cure for diabetes without relying on exogenous insulin. Although reports of clinical trials show promise in reducing insulin dependency in patients, their safety and efficacy needs to be further studied to promote their use as a long-term solution to cure diabetes. Full article