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16 pages, 2754 KB  
Article
Ex Situ Liver Splitting During Hypothermic Oxygenated Perfusion: Mechanistic Insights into Mitochondrial Injury and FMN-Based Viability Assessment
by Rebecca Panconesi, Geofia S. Crasta, Hiroshi Horie, Chunbao Jiao, Keyue Sun, Sangeeta Satish, F. Selin Yildirim, Omer F. Karakaya, Fernanda Walsh Fernandes, Koki Takase, Nasim Eshraghi, Tobias Diwan, Kumaran Shanmugarajah, Chase J. Wehrle, Charles Miller, Sapana Verma, Alejandro Pita, Masato Fujiki, Koji Hashimoto and Andrea Schlegel
Livers 2026, 6(5), 83; https://doi.org/10.3390/livers6050083 - 24 Aug 2026
Abstract
Background/Objectives: Hypothermic oxygenated perfusion (HOPE) improves graft preservation in whole liver transplantation, yet evidence supporting its use in split grafts for pediatric transplantation remains limited. Mitochondrial injury assessed during HOPE through spectroscopic measurement of flavin mononucleotide (FMN) has been associated with graft [...] Read more.
Background/Objectives: Hypothermic oxygenated perfusion (HOPE) improves graft preservation in whole liver transplantation, yet evidence supporting its use in split grafts for pediatric transplantation remains limited. Mitochondrial injury assessed during HOPE through spectroscopic measurement of flavin mononucleotide (FMN) has been associated with graft function in whole-organ transplantation. Here, we evaluate a human liver assessment pathway integrating mitochondrial viability testing with ex situ liver splitting during HOPE. Methods: Following standard procurement and transport, twelve discarded extended criteria human donor livers were evaluated for split feasibility and underwent HOPE (VitaSmart®). Donors were between 40 and 72 years with a BMI of 23.4–42.7 kg/m2 and 4–22 h of cold storage prior to HOPE. After two hours of portal-venous HOPE treatment, different split procedures were performed. Perfusates and tissues were analyzed for mitochondrial injury and inflammatory responses. Results: Four grafts met previously reported FMN thresholds for transplant suitability in whole-graft HOPE studies (FMN ≤ 0.02 μg/mL at 60 min). Livers with low FMN release demonstrated lower Complex I and II injury, greater ATP recovery, and reduced inflammatory signaling during HOPE. Conclusions: These findings indicate that mitochondrial injury during HOPE can be monitored during ex situ splitting and suggest that FMN-guided metabolic assessment may support graft evaluation within split liver transplantation pathways for pediatric recipients. Full article
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15 pages, 1688 KB  
Article
The Association of Flavin Mononucleotide and Lactate During Normothermic Regional Perfusion with Post-Transplant Liver Outcomes: An Exploratory Study
by Raphaël M. J. Fischer, Claire Cywes, Olivia Ong, Nicolas Muñoz, Sardar Din, Tobenna Ibeabuchi, Isabela Brown-Soler, Nadim Mahmud, Kelly Cederquist, Georgeine Smith, Stephanie Benko, Chase J. Wehrle, Elizabeth M. Sonnenberg, Matthew H. Levine, Samir Abu-Gazala, James F. Markmann, Kim M. Olthoff, Abraham Shaked, Frederick Vyas, Marty Sellers, Jeroen de Jonge, Keyue Sun, Andrea Schlegel and Peter L. Abtadd Show full author list remove Hide full author list
Medicina 2026, 62(9), 1622; https://doi.org/10.3390/medicina62091622 - 22 Aug 2026
Abstract
Background and Objectives: Normothermic regional perfusion (NRP) is an effective technique to improve recipient outcomes. However, no valid methods for determining liver viability exist. Identifying relevant biological markers with clinical correlation to liver viability and recipient clinical outcomes is imperative to improve [...] Read more.
Background and Objectives: Normothermic regional perfusion (NRP) is an effective technique to improve recipient outcomes. However, no valid methods for determining liver viability exist. Identifying relevant biological markers with clinical correlation to liver viability and recipient clinical outcomes is imperative to improve decision-making. Materials and Methods: Fifty-four donors undergoing NRP and their recipients were included. FMN was measured at the start, 1 h, and end of NRP. Lactate was measured at the start, 30, 60, and 90 min of NRP. Primary outcomes were early allograft function using the early allograft dysfunction (EAD) criteria and the model for early allograft function (MEAF). Secondary outcomes included the association with donor warm ischemia time (DWIT), stratified by 30 min. Spearman’s rho assessed correlations. Results: Forty (74%) livers were transplanted, with 5 (12.5%) recipients developing EAD and the mean MEAF score was 3.13 (1.49). FMN at all time points was significantly greater in the EAD group compared to the non-EAD group and was significantly correlated with the MEAF score (Peak FMN: rho = 0.507, p = 0.001). FMN during perfusion did not differ between DWIT < and ≥30 min. Lactate levels were similar across all groups and did not discriminate for adverse allograft outcomes. However, lactate levels during perfusion were higher in the DWIT ≥ 30 min group. Conclusions: These findings suggest that during NRP, elevated FMN, but not lactate, is associated with early allograft function. Full article
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13 pages, 681 KB  
Review
Hepatitis C in Chronic Kidney Disease After the DAA Revolution: Clinical Decisions, Transplantation, and Implementation Challenges
by Mostafa Mohrag, Ali Someili, Erwa Elmakki and Mohammed Abdulrasak
J. Clin. Med. 2026, 15(17), 6504; https://doi.org/10.3390/jcm15176504 - 22 Aug 2026
Abstract
Direct-acting antiviral (DAA) therapy has dramatically transformed the management of hepatitis C virus (HCV) infection in chronic kidney disease (CKD). Severe renal impairment and dialysis dependence are no longer considered major barriers to virologic cure. The main difficulties have shifted toward efficient diagnosis, [...] Read more.
Direct-acting antiviral (DAA) therapy has dramatically transformed the management of hepatitis C virus (HCV) infection in chronic kidney disease (CKD). Severe renal impairment and dialysis dependence are no longer considered major barriers to virologic cure. The main difficulties have shifted toward efficient diagnosis, choosing the regimen in the presence of cirrhosis and drug interactions, coordinating treatment with kidney transplantation, managing HCV-associated immune-complex kidney disease, and providing treatment in dialysis and resource-limited settings. This narrative review aims to discuss these issues in a decision-oriented manner, using verified guidelines, systematic reviews, important clinical trials, transplant cohorts, and studies of cryoglobulinemic disease, while explicitly comparing the strength and consistency of the underlying evidence and highlighting areas of genuine clinical uncertainty. Present evidence supports using the recommended DAA regimens without renal dose adjustment, while ribavirin needs dose modification when kidney function is reduced and can result in hemolytic anemia. Kidneys from HCV-viremic donors can be transplanted to recipients without HCV infection when proper informed consent, rapid access to DAA treatment, and organized post-transplant monitoring are available, although the minimum effective duration of peri-transplant antiviral prophylaxis remains unresolved. Antiviral therapy is the first-line treatment for HCV-associated glomerular disease, while rituximab-based immunosuppression is largely reserved for severe, rapidly progressive, or persistent cryoglobulinemic vasculitis. Future progress will depend less on proving antiviral efficacy and more on closing the gaps between screening, confirmatory testing, starting treatment, transplantation pathways, and long-term follow-up, gaps that stem from inequities in diagnostic infrastructure, drug reimbursement, and healthcare-system organization as much as from any remaining biomedical uncertainty. Full article
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13 pages, 277 KB  
Article
Integrated Serum and Urinary Metabolomics Reveal Distinct Signatures of Kidney Graft Function—A Single-Center Cohort Study
by Cezar Valeriu Băluță, Lucian Siriteanu, Ionuț Nistor, Luminița Voroneanu, Simona Mihaela Hogas, Andreea Covic, Călin Namolovan, Raluca Erika Irimie Băluță, Radu Gavril, Calin Deleanu, Alina Nicolescu, Mehmet Kanbay and Adrian Covic
Biomedicines 2026, 14(8), 1875; https://doi.org/10.3390/biomedicines14081875 (registering DOI) - 21 Aug 2026
Viewed by 191
Abstract
Background/Objectives: Kidney transplantation remains the gold standard treatment of end-stage kidney disease; however, its recipients exhibit mixed clinical trajectories, with variable renal function and proteinuria evolution over time. Currently used methods to screen these changes are associated with possible adverse effects and [...] Read more.
Background/Objectives: Kidney transplantation remains the gold standard treatment of end-stage kidney disease; however, its recipients exhibit mixed clinical trajectories, with variable renal function and proteinuria evolution over time. Currently used methods to screen these changes are associated with possible adverse effects and limitations. Methods: In this single-center cohort study, 174 adult kidney transplant recipients were enrolled between January 2024 and January 2025 and followed for 12 months. Patients underwent serum and urinary metabolomic profiling using nuclear magnetic resonance (NMR) spectroscopy. Furthermore, clinical and biological data were collected, allowing for assessment of changes in renal function and proteinuria, with patient stratification based on outcome trends. Results: Serum metabolomic profiles were linked to renal outcomes. For ΔeGFR, valine differed between patients with positive and negative trajectories, while GlycA, GlycB and Glyc/SPC were associated with ΔeGFR in adjusted models. For Δproteinuria, GlycA, VLDL particles and triglycerides showed correlations, while glucose differed between patients with improving and worsening proteinuria. In adjusted models, isoleucine, alanine, GlycA and Glyc/SPC were associated with Δproteinuria. Urinary metabolomic profiles showed fewer associations. Dimethylamine and urinary creatinine were associated with ΔeGFR in adjusted models, while acetic acid differed between proteinuria groups. No urinary metabolite was associated with Δproteinuria after adjustment. Conclusions: Overall, metabolomic changes were connected with renal outcomes in kidney transplant patients, with distinct but partially overlapping patterns for ΔGFR and Δproteinuria. Serum findings were more consistent, while urinary associations were more limited. Further longitudinal and externally validated studies are required to confirm these observations and explore the potential of this metabolomic approach in the search for novel biomarkers. Full article
31 pages, 1865 KB  
Article
Topical Magnesium Orotate Lipogel in Kidney Transplant Recipients with Persistent Hypomagnesemia: Formulation Development and Pilot Clinical Study
by Corina Moisa, Florin Bănică, Ioana Adela Rațiu, Octavia Gligor, Laura Grațiela Vicaș, Cristian Adrian Rațiu, Mădălin Florin Ganea, Csaba Nagy, Anamaria Ratiu, Edy Hagi Islai and Mariana Ganea
Nutrients 2026, 18(16), 2740; https://doi.org/10.3390/nu18162740 - 21 Aug 2026
Viewed by 193
Abstract
Background: In solid-organ transplant recipients, hypomagnesemia is a frequent and persistent complication, predominantly related to long-term use of calcineurin inhibitors. Oral magnesium supplementation is often ineffective due to poor adherence, gastrointestinal adverse effects, and high treatment costs. Objectives: This pilot study [...] Read more.
Background: In solid-organ transplant recipients, hypomagnesemia is a frequent and persistent complication, predominantly related to long-term use of calcineurin inhibitors. Oral magnesium supplementation is often ineffective due to poor adherence, gastrointestinal adverse effects, and high treatment costs. Objectives: This pilot study aimed to (i) develop a topical magnesium formulation for use in renal transplant recipients with persistent hypomagnesemia; (ii) evaluate the influence of formulation excipients on magnesium release from pharmaceutical preparations; and (iii) preliminarily assess the clinical outcomes, functional parameters, patient satisfaction, and tolerability associated with topical magnesium lipogel use in renal transplant recipients with persistent hypomagnesemia. Materials and Methods: Three lipogel formulations containing magnesium orotate, citrate, or sulfate were prepared and characterized in terms of organoleptic properties, pH, colloidal stability, and rheological behavior. In vitro magnesium release was evaluated using Franz diffusion cells. The formulation demonstrating the most favorable release profile, magnesium orotate lipogel, was administered twice daily for two months to 21 renal transplant recipients with persistent hypomagnesemia who had shown inadequate response, intolerance, or non-adherence to oral magnesium supplementation. Laboratory parameters were assessed at baseline and after treatment. Patient satisfaction was evaluated using the Lübeck questionnaire, while physical activity and exercise capacity were assessed using the International Physical Activity Questionnaire (IPAQ) and metabolic equivalent task (MET) calculations. Results: Franz cell studies demonstrated superior magnesium release from the magnesium orotate lipogel compared with the other formulations. After two months, serum magnesium levels were higher than baseline (1.554 ± 0.124 vs. 1.448 ± 0.111 mg/dL, p < 0.001), although they remained below the normal reference range. No significant changes were observed in eGFR or hsCRP. Moderate-intensity physical activity increased significantly (310.475 ± 92.505 vs. 279.286 ± 89.907 MET-min/week, p < 0.001), while vigorous-intensity activity did not change significantly. No relevant adverse effects were reported. Patient satisfaction was high across all evaluated domains, including practicability (86.6%), efficacy (96.4%), tolerability (97.1%), and trust in medical professionals (97.6%). Conclusions: In this pilot study, topical magnesium orotate lipogel was well tolerated and accepted by renal transplant recipients with persistent hypomagnesemia. Serum magnesium levels and moderate physical activity improved over the two-month observation period, although magnesium levels remained below the normal range. These preliminary findings warrant confirmation in larger, randomized, placebo-controlled studies. Full article
(This article belongs to the Special Issue Magnesium in Aging, Health and Diseases)
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13 pages, 3214 KB  
Article
National-Level Prevalence of Overweight and Obesity Among Liver Transplant Recipients in the USA, 1988–2022, and Projections to 2050
by Sarpong Boateng, Frhaan Zahrawi, Prince Ameyaw, Mansoor Jalal Zai, Mohammad-Javad Khosousi, Vandana Khungar and Bubu A. Banini
Livers 2026, 6(4), 81; https://doi.org/10.3390/livers6040081 - 21 Aug 2026
Viewed by 136
Abstract
Background/Objectives: As indications of liver transplantation evolve and the burden of obesity rises in the general population, a clear understanding of weight trends among liver transplant (LT) recipients is needed to inform evidence-based guidance for obesity prevention and management across the transplant continuum. [...] Read more.
Background/Objectives: As indications of liver transplantation evolve and the burden of obesity rises in the general population, a clear understanding of weight trends among liver transplant (LT) recipients is needed to inform evidence-based guidance for obesity prevention and management across the transplant continuum. The objective of this study was to characterize national trends in body mass index (BMI) among adult liver transplant recipients and to project future trajectories, with attention to key demographic and disease-related subgroups. Methods: Using national-level data on 176,891 LT recipients from the United Network for Organ Sharing (UNOS)/Organ Procurement and Transplantation Network (OPTN) database between 1988 and 2022, we analyzed trends in BMI among adult LT recipients, applying linear regression to evaluate temporal trends and identify changes in trajectories. We stratified results by sex, race/ethnicity, age, and liver disease etiology, and derived BMI projections until 2050. Results: We observed that from 1988 to 2022, the mean BMI increased from 24.7 kg/m2 (representing normal weight) to 28.9 kg/m2 (representing overweight) (p < 0.001). There was a significant decline in the number of LT recipients classified as underweight or normal weight, with a reciprocal increase in overweight and all obesity categories. Based on current trends, the mean BMI of LT recipients is projected to reach 30.1 kg/m2 (representing class I obesity) by 2050. Conclusions: Overall, overweight and obesity rates among adult LT recipients have risen dramatically over three decades. Effective prevention and treatment strategies for excess weight are much needed before and after LT. Full article
(This article belongs to the Special Issue Transforming Liver Transplantation: Breakthroughs and Boundaries)
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13 pages, 882 KB  
Article
Pharmacogenetic Profiling of Allogeneic Stem Cell Transplantation Patients: An Exploratory Descriptive Study
by Lea P. A. Timmann, Pauline Lanting, Linde M. Morsink, Marcel Nijland, Laura B. Bungener, Gerwin A. Huls, Daan J. Touw, Thijs H. Oude Munnink and Carolien M. Woolthuis
Hemato 2026, 7(3), 28; https://doi.org/10.3390/hemato7030028 - 21 Aug 2026
Viewed by 87
Abstract
Background/Objectives: Patients receiving allogeneic hematopoietic stem cell transplantation (alloHCT) for acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) are at high risk for severe disease and treatment-related complications and toxicities. Pharmacogenetic studies suggest that genetic variants can alter the response to [...] Read more.
Background/Objectives: Patients receiving allogeneic hematopoietic stem cell transplantation (alloHCT) for acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) are at high risk for severe disease and treatment-related complications and toxicities. Pharmacogenetic studies suggest that genetic variants can alter the response to several drugs critical to alloHCT outcomes, including tacrolimus and cyclophosphamide, potentially impacting toxicity and treatment outcomes. Methods: To assess the frequency of pharmacogenetic variants in AML/ALL patients undergoing alloHCT, we used a validated 11-gene pharmacogenetic panel in an exploratory descriptive study. We retrospectively genotyped 142 AML/ALL patients including two atypical chronic myeloid leukemia (aCML) patients, ≥18 years, who underwent alloHCT at our center between January 2020 and June 2024. Results obtained from 470 individuals in the Lifelines NEXT population cohort were used as controls. Results: Almost all patients carried at least one pharmacogenetic variant (97.2%), with a mean of 3.2 (standard deviation = 1.5) variants per patient. Variants known to influence tacrolimus metabolism (CYP3A4 and CYP3A5) were present in 26.8% of patients. Variants known to influence cyclophosphamide metabolism (CYP2B6, CYP2C9, CYP2C19) were present in 81.7% of patients. Variant frequencies did not significantly differ from controls. Conclusions: Actionable pharmacogenetic variants are highly prevalent in alloHCT-recipients. Future studies should investigate whether genotype-guided drug selection and dosing could improve outcomes in alloHCT recipients. Full article
(This article belongs to the Section Leukemias)
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19 pages, 287 KB  
Article
Nutritional Status, Dietary Intake and Immunosuppressive Therapy in Kidney Transplant Recipients: Differences Between Early and Late Post-Transplant Period—A Cross-Sectional Pilot Study
by Aleksandra Anna Kajdas, Dorota Szostak-Węgierek, Krzysztof Krasuski, Dorota Miszewska-Szyszkowska and Magdalena Durlik
Nutrients 2026, 18(16), 2725; https://doi.org/10.3390/nu18162725 - 20 Aug 2026
Viewed by 280
Abstract
Background/Objectives: Kidney transplantation is associated with profound metabolic and nutritional changes, particularly across different post-transplant periods. This study aimed to evaluate differences in nutritional status, dietary intake, and immunosuppressive therapy between recipients in the early and late post-transplant period. Materials and Methods: This [...] Read more.
Background/Objectives: Kidney transplantation is associated with profound metabolic and nutritional changes, particularly across different post-transplant periods. This study aimed to evaluate differences in nutritional status, dietary intake, and immunosuppressive therapy between recipients in the early and late post-transplant period. Materials and Methods: This cross-sectional pilot study presents an analysis of baseline data obtained from a prospective cohort of 38 kidney transplant recipients divided into early (≤1 year post-transplantation; n = 15) and late (>1 year post-transplantation; n = 23) post-transplant groups. Nutritional status was assessed using anthropometric and laboratory measurements, bioelectrical impedance analysis (BIA), and Nutritional Risk Screening 2002 (NRS-2002). Dietary intake was assessed using the Food Frequency Questionnaire-6 (FFQ-6) and a 3-day dietary record. Information regarding immunosuppressive therapy was obtained from medical records and verified at routine clinic visits. Results: The groups did not differ significantly with respect to sociodemographic characteristics, comorbidities, anthropometric measurements, body composition, and nutritional risk. No significant differences were observed in body weight, body mass index (BMI), body composition parameters, or most laboratory measurements. Early post-transplant recipients exhibited significantly higher non-high-density lipoprotein (non-HDL) cholesterol concentrations (153.3 ± 37.5 vs. 111.1 ± 50.8 mg/dL; p = 0.040), higher tacrolimus trough concentrations (11.2 ± 5.2 vs. 4.6 ± 1.1 ng/mL; p = 0.0001), and lower serum magnesium concentrations (1.64 ± 0.13 vs. 1.94 ± 0.15 mg/dL; p = 0.009) than late post-transplant recipients. No statistically significant differences were observed for most assessed dietary habits, except for the more frequent addition of sugar to beverages among the early post-transplant group (p = 0.048). Qualitative assessment of 3-day dietary records showed a tendency toward more regular meals and greater dietary variety among early post-transplant recipients. This group also received significantly higher tacrolimus trough concentrations and higher prednisone-equivalent and mycophenolate doses than recipients in the late post-transplant period. Conclusions: In this pilot study, the observed differences between early and late post-transplant recipients concerned primarily immunosuppressive exposure and selected metabolic parameters, while no statistically significant differences were identified for most measures of nutritional status or dietary intake. Given the small sample size and the exploratory nature of the study, these findings should be considered preliminary and hypothesis-generating rather than confirmatory. Larger, adequately powered prospective studies are needed to validate these observations and further evaluate nutritional and metabolic changes across the post-transplant course. Full article
13 pages, 1478 KB  
Article
Discharge AI-ECG-Derived Age and Incidence of Cardiac Allograft Vasculopathy at 3 Years: A Pilot Study
by Andrea Muniz, Yugant Khand, Vidit Yadav, Aarti Desai, Laxmi Raj Bangari, Surbhi Dadwal, Jose Ruiz, Devora Leventhal and Rohan Goswami
J. Cardiovasc. Dev. Dis. 2026, 13(8), 400; https://doi.org/10.3390/jcdd13080400 - 20 Aug 2026
Viewed by 133
Abstract
Cardiac allograft vasculopathy (CAV) remains a leading cause of graft failure after heart transplantation, yet an early, non-invasive risk stratification tool is not available. Artificial intelligence electrocardiography (AI-ECG) can estimate biological heart age, and it has been associated with cardiovascular risk. Its deviation [...] Read more.
Cardiac allograft vasculopathy (CAV) remains a leading cause of graft failure after heart transplantation, yet an early, non-invasive risk stratification tool is not available. Artificial intelligence electrocardiography (AI-ECG) can estimate biological heart age, and it has been associated with cardiovascular risk. Its deviation with chronological age, called delta age, and its utility in the prediction of CAV has never been explored. We conducted a retrospective single-center study for heart transplant recipients bridged with Impella 5.5 (Abiomed, Danvers, MA, USA) at Mayo Clinic Florida (2020–2023). ΔAge was calculated at discharge and 1-year post-transplant. The primary outcome was confirmed CAV at 1 year. Univariate and multivariable logistic regression models were used to assess the independent association between the ΔAge and the development of CAV, with discrimination evaluated by AUC and internally validated via bootstrap resampling (2000 iterations). Fifty patients were reviewed. CAV developed in 13 (26%) patients in 3 years. CAV+ patients had a significantly higher ΔAge at discharge compared to CAV- patients (median −1.0 vs. −11.0 years, p = 0.0023) and at 1 year (median +7.0 vs. −4.0 years, p = 0.0080). On univariate analysis, ΔAge at discharge was a significant predictor of the development of CAV (OR 1.084 per year, AUC 0.788). On multivariable adjustment, ΔAge at discharge remained an independent predictor (adjusted OR 1.138, 95% CI 1.023–1.265, p = 0.018, and model AUC 0.859). ΔAge at discharge is a novel and potential predictor of the development of CAV within 3 years. These findings support the integration of AI-ECG into post-transplant surveillance as a scalable, low-cost tool. Full article
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22 pages, 1326 KB  
Review
Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification—A Narrative Review
by Caterina Nela Dumitru, Teodora Marcu, Alina Oana Dumitru, Simona Steliana Tudor, Ionela Daniela Ferțu, Alina-Mihaela Elisei and Larisa Goroftei
Pharmaceuticals 2026, 19(8), 1313; https://doi.org/10.3390/ph19081313 - 20 Aug 2026
Viewed by 268
Abstract
Background: Berberine, an isoquinoline alkaloid present in Berberis spp., Coptis chinensis and Hydrastis canadensis, is among the most widely consumed metabolic-health supplements, popularized as “nature’s Ozempic”. Concurrent, often undisclosed use with prescription drugs is common in older adults, yet berberine is far [...] Read more.
Background: Berberine, an isoquinoline alkaloid present in Berberis spp., Coptis chinensis and Hydrastis canadensis, is among the most widely consumed metabolic-health supplements, popularized as “nature’s Ozempic”. Concurrent, often undisclosed use with prescription drugs is common in older adults, yet berberine is far from inert. Objective: To synthesize the evidence on berberine as a perpetrator of supplement–drug interactions, propose a four-axis mechanistic taxonomy, with product quality treated separately as a modifier of exposure rather than as a mechanism, and derive a clinically actionable risk-stratification framework. Methods: Structured narrative review, prepared per the SANRA quality criteria; PubMed/MEDLINE, Scopus, Web of Science and Embase were searched up to May 2026. Results: Despite very low systemic exposure (oral bioavailability 0.68% in rats; low ng/mL plasma concentrations in humans), high luminal, enterocytic and hepatic concentrations generate interaction liability, documented in humans for a few pairs and mechanistic for most, along four mechanistic axes: inhibition, and transcriptional induction, of CYP3A4, with CYP2D6/CYP2C9 inhibition that is quasi-irreversible through a metabolite-intermediate complex; transporter modulation (P-glycoprotein, OCT1/OCT2, and MATE1); pharmacodynamic additivity (hypoglycemia, hypotension, and QT prolongation); and microbiome- and gut-barrier-mediated effects, the last of these being a candidate axis rather than a demonstrated one. Product-quality variability is treated separately, as a modifier of exposure. The clinical anchor is increased cyclosporine exposure in renal-transplant recipients (AUC +34.5%; trough 29.3% above control). These elements are integrated into a three-tier risk-stratification framework that combines perpetrator potency, victim-drug vulnerability, and patient vulnerability, with each tier being linked to a defined pharmacy action. Conclusions: In patients on multiple medications, and particularly when berberine is co-administered with drugs of narrow therapeutic index, it should be managed as an active pharmacological perpetrator rather than as an inert supplement. Unstandardized product quality and an unsettled European regulatory framework, under which national limits differ by more than an order of magnitude, further widen the uncertainty around the dose actually delivered. Berberine use should therefore be elicited routinely at medication reconciliation and stratified by mechanism, by victim-drug vulnerability, and by patient risk, with particular attention to metabolic self-medication in the GLP-1 era. Full article
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16 pages, 3139 KB  
Article
Serial Cardiac Troponin I Kinetics Do Not Improve Detection of Acute Cellular Rejection Beyond Concurrent Troponin Levels After Heart Transplantation
by Michał Ochman, Barbara Bilnik, Magdalena Cielecka and Michał Zakliczyński
J. Clin. Med. 2026, 15(16), 6444; https://doi.org/10.3390/jcm15166444 - 20 Aug 2026
Viewed by 148
Abstract
Background/Objectives: High-sensitivity cardiac troponin I (hs-cTnI) has shown inconsistent diagnostic performance for acute cellular rejection (ACR) after heart transplantation. We evaluated whether time-normalized hs-cTnI kinetics provide incremental diagnostic value beyond the concurrent concentration for detecting ACR grade ≥ 2R and whether this [...] Read more.
Background/Objectives: High-sensitivity cardiac troponin I (hs-cTnI) has shown inconsistent diagnostic performance for acute cellular rejection (ACR) after heart transplantation. We evaluated whether time-normalized hs-cTnI kinetics provide incremental diagnostic value beyond the concurrent concentration for detecting ACR grade ≥ 2R and whether this association varies with time after transplantation. Methods: This retrospective single-center study included 1237 biopsy episodes from 139 heart transplant recipients. Two generalized linear mixed-effects logistic regression models with patient-specific random intercepts were compared. M1 included concurrent log2-transformed hs-cTnI, whereas M2 additionally included the time-normalized change in log2-transformed hs-cTnI per 7 days. Discrimination was assessed using leave-one-patient-out cross-validation with patient-level cluster bootstrap confidence intervals. Exploratory analyses examined early (≤90 days), late (>90 days), and continuous post-transplant time. Results: In the overall cohort, M1 showed modest discrimination (AUC 0.641, 95% CI 0.592–0.689), whereas M2 provided no improvement (AUC 0.635; ΔAUC −0.007). Within 90 days, neither model was informative (M1 AUC 0.503; M2 AUC 0.494). Beyond 90 days, M1 showed moderate discrimination (AUC 0.758, 95% CI 0.664–0.838), but M2 again provided no improvement (AUC 0.746; ΔAUC −0.012). Continuous-time modeling showed that the association between concurrent hs-cTnI and ACR strengthened with increasing time after transplantation, whereas the kinetic term remained non-informative. Conclusions: Time-normalized hs-cTnI kinetics did not provide incremental diagnostic value beyond concurrent hs-cTnI. Concurrent hs-cTnI may warrant further evaluation as an adjunctive late-period marker, but the 90-day threshold remains exploratory and requires external validation. Neither hs-cTnI concentration nor its kinetics should replace endomyocardial biopsy. Full article
(This article belongs to the Section Cardiology)
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10 pages, 616 KB  
Article
Association Between Initial Serum Galactomannan Level and Radiological and Clinical Outcomes of Invasive Pulmonary Aspergillosis in Patients with Hematological Malignancies
by Ibrahim Al-Busaidi and Mariam Al-Muqbali
LabMed 2026, 3(3), 21; https://doi.org/10.3390/labmed3030021 - 20 Aug 2026
Viewed by 108
Abstract
Invasive pulmonary aspergillosis (IPA) is a major cause of morbidity and mortality in patients with hematological malignancies. Serum galactomannan (GM) is widely used for diagnosis, but the prognostic value of the initial GM level is not well established. We aimed to assess the [...] Read more.
Invasive pulmonary aspergillosis (IPA) is a major cause of morbidity and mortality in patients with hematological malignancies. Serum galactomannan (GM) is widely used for diagnosis, but the prognostic value of the initial GM level is not well established. We aimed to assess the association between the initial serum GM level at IPA diagnosis and the radiological and clinical outcomes at 42 and 90 days. We retrospectively reviewed adult patients with hematological malignancies, including hematopoietic stem cell transplant (HSCT) recipients, diagnosed with proven or probable IPA at Sultan Qaboos University Hospital between 2014 and 2017, according to the 2008 EORTC/MSG criteria. Demographic, microbiological, radiological, and clinical data were collected. Outcomes were assessed using dichotomous and balanced multi-level GM cut-off categories. Seventy-eight patients were included. The median age was 44.5 years (range 18–76); 53.8% were male. Lymphoma (30.7%) and acute leukemia (25.6%) were the leading underlying diseases. Voriconazole was the most frequently used antifungal agent (74.3%). Prolonged neutropenia was present in 61.9%, and 30.7% had received HSCT. The mean serum GM at diagnosis was 1.95 (range 0.5–7.89). At 90 days, follow-up imaging showed a complete radiological response in 22 patients (29.3%), a partial response in 28 (37.3%), and no response in 25 (33.3%). Overall, 90-day mortality was 35.9%. There was no statistically significant association between initial GM level and 90-day mortality across categories (GM 0.5–3.0: 34.2% mortality; GM > 3.0: 60%; p = 0.243). Within the GM 0.5–3.0 group, complete radiological response was strongly associated with survival (95.2% alive at 90 days; p < 0.001). The initial serum GM level was not significantly associated with clinical or radiological outcomes at 42 or 90 days in patients with hematological malignancies and IPA. However, an early complete radiological response was strongly associated with improved survival, supporting the use of follow-up CT chest imaging to guide management. Full article
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12 pages, 224 KB  
Article
Pancreas Transplant Recipients with and Without Pretransplant Alcohol Use Disorder: A Real-World Cohort Study
by Arkadeep Dhali, Jyotirmoy Biswas, Sajjad Ahmed Khan, Fayaz Khan, Saikat Mandal, Ashish Sharma, Dushyant Singh Dahiya and Manideepa Maji
Med. Sci. 2026, 14(4), 497; https://doi.org/10.3390/medsci14040497 - 19 Aug 2026
Viewed by 141
Abstract
Background: Alcohol use disorder (AUD) is generally regarded as a relative contraindication to pancreas transplantation. Yet the effect of documented AUD before transplantation on long-term results after pancreas transplantation is still poorly understood. Therefore, we used a large real-world electronic health records database [...] Read more.
Background: Alcohol use disorder (AUD) is generally regarded as a relative contraindication to pancreas transplantation. Yet the effect of documented AUD before transplantation on long-term results after pancreas transplantation is still poorly understood. Therefore, we used a large real-world electronic health records database to compare the three-year outcomes among pancreas transplant recipients who had and who had not had documented AUD before transplantation. Methods: We carried out a retrospective cohort study involving propensity score matching using the TriNetX US Collaborative Network. Each adult patient who had a documented case of alcohol use disorder (ICD-10-CM codes F10.1/F10.2) before transplantation was paired one to one with a patient who did not have such a disorder, matching them on demographic characteristics, comorbidities, transplant-related factors, medications, body mass index, and glycated hemoglobin. The outcomes were evaluated from one day after transplantation up to three years later and comprised all-cause mortality, emergency visits, transplant complications, cachexia, severe protein–calorie malnutrition, pain, vitamin deficiencies, iron deficiency anaemia, diarrhea, and adult failure to thrive. Results: Out of 14,367 eligible recipients, propensity score matching resulted in 439 patients in each group. Pretransplant AUD was linked to a significantly higher rate of all-cause mortality (15.1% compared with 8.5%; risk ratio [RR] 1.78, 95% CI 1.22–2.60; hazard ratio [HR] 1.86, 95% CI 1.25–2.78; p = 0.002). Cachexia affected 5.2% rather than 2.5% (RR 2.09, 95% CI 1.03–4.24; HR 2.16, 95% CI 1.06–4.44; p = 0.036), while diarrhea occurred in 39.6% compared with 28.2% (RR 1.40, 95% CI 1.16–1.69; HR 1.54, 95% CI 1.22–1.94; p < 0.001). There were no significant differences in the case of emergency visits (49.0% versus 44.6%; p = 0.199), transplant complications (11.1% versus 14.4%; p = 0.163), severe protein–calorie malnutrition (12.1% versus 8.9%; p = 0.123), pain (59.0% versus 54.7%; p = 0.195), vitamin deficiencies (31.4% versus 29.4%; p = 0.509), iron deficiency anemia (21.2% versus 21.9%; p = 0.805), or adult failure to thrive (7.3% versus 4.3%; p = 0.061). Conclusions: The presence of a history of alcohol use disorder (AUD) before transplantation was found to be independently linked to a higher three-year mortality rate, as well as the occurrence of cachexia and diarrhea after pancreas transplantation, but it was not associated with an increased number of coded transplant complications or most of the other adverse outcomes following the procedure. These results indicate that pancreas transplant recipients with a history of AUD should have enhanced monitoring in the areas of nutrition, the gastrointestinal system, and addiction. Full article
(This article belongs to the Section Hepatic and Gastroenterology Diseases)
12 pages, 6683 KB  
Case Report
Dual Invasive Fungal Infections After Kidney Transplantation: A Case Report
by Layan Akkielah, Ahmed Bishara, Leigh J. Sowerby, John Johnson, Matthew A. Weir, Michael Chiu, Laila Alshafai, Michael Silverman and Mohammad Reza Rahimi Shahmirzadi
J. Fungi 2026, 12(8), 621; https://doi.org/10.3390/jof12080621 - 19 Aug 2026
Viewed by 195
Abstract
Donor-derived infections (DDIs), particularly fungal DDIs, are uncommon but serious complications of solid organ transplantation. We report a case of a 52-year-old woman who underwent deceased donor kidney transplantation complicated by probable donor-derived Candida albicans candidemia with native aortic valve endocarditis, managed medically [...] Read more.
Donor-derived infections (DDIs), particularly fungal DDIs, are uncommon but serious complications of solid organ transplantation. We report a case of a 52-year-old woman who underwent deceased donor kidney transplantation complicated by probable donor-derived Candida albicans candidemia with native aortic valve endocarditis, managed medically with prolonged echinocandin therapy followed by suppressive fluconazole. Approximately 14 months post-transplant, she developed progressive rhino-orbital mucormycosis due to Rhizopus oryzae, requiring extensive surgical debridement and prolonged antifungal therapy. Initial treatment with liposomal amphotericin B was limited by nephrotoxicity, prompting transition to isavuconazole for long-term management. Immunosuppression was discontinued to control infection, resulting in graft failure. This case illustrates the complex interplay between donor-derived infection, antifungal exposure, and immunosuppression in transplant recipients. It highlights the potential contribution of antifungal selective pressure to breakthrough mold infections and underscores the importance of early recognition, aggressive multidisciplinary management, and individualized antifungal strategies in this high-risk population. Full article
(This article belongs to the Section Fungal Pathogenesis and Disease Control)
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22 pages, 955 KB  
Article
Associations of IL-2, IL-6 and IL-10 Gene Polymorphisms with Biochemical Parameters and Calcineurin Inhibitor Dosing in Kidney Transplant Recipients
by Anna Bogacz, Paweł Szakoła, Monika Kuciak, Jerzy Sieńko, Maciej Kotowski, Grażyna Kurzawińska, Wojciech Łabędź, Aleksandra E. Mrozikiewicz, Agata Urbaniak, Piotr Olbromski and Dorota Formanowicz
Biomedicines 2026, 14(8), 1858; https://doi.org/10.3390/biomedicines14081858 - 18 Aug 2026
Viewed by 258
Abstract
Background/Objectives: Kidney graft dysfunction remains a major challenge limiting long-term transplant survival despite advances in immunosuppressive therapy. Cytokine signaling pathways have been implicated in the regulation of alloimmune responses and chronic inflammation, but their contribution to long-term graft function and immunosuppressant pharmacokinetics [...] Read more.
Background/Objectives: Kidney graft dysfunction remains a major challenge limiting long-term transplant survival despite advances in immunosuppressive therapy. Cytokine signaling pathways have been implicated in the regulation of alloimmune responses and chronic inflammation, but their contribution to long-term graft function and immunosuppressant pharmacokinetics remains incompletely understood. This study investigated associations among selected cytokine gene polymorphisms (IL-2 −330T>G, IL-6 −174G>C, and IL-10 −1082A>G), biochemical and hematological parameters, and calcineurin inhibitor (tacrolimus and cyclosporine) dosing in kidney transplant recipients. Methods: A total of 394 kidney transplant recipients receiving tacrolimus or cyclosporine were enrolled. Genotyping of IL-2 rs2069762, IL-6 rs1800795 and IL-10 rs1800896 was performed using real-time PCR. Clinical, biochemical, and pharmacokinetic data were analyzed using univariate and multivariate statistical models adjusted for relevant demographic and clinical covariates. ResultsIL-2 rs2069762 and IL-6 rs1800795 polymorphisms were not associated with clinically relevant differences in biochemical parameters, calcineurin inhibitor dosing, or transplant outcomes. For IL-10 rs1800896, no statistically significant associations were observed with cyclosporine A blood levels, dose, or C/D ratio. Among tacrolimus-treated patients, the regression model for the C/D ratio was borderline significant (F(2,207) = 3.048, p = 0.050, R2 = 0.029). However, the genotype-specific association for the heterozygous GA genotype versus AA was not statistically significant in the unadjusted model (B = −0.462, 95% CI: −0.97 to 0.04, p = 0.072) or after adjustment for age, sex, and time since transplantation (B = −0.450, 95% CI: −0.95 to 0.05, p = 0.078). Although univariate analyses identified associations between IL-10 rs1800896 and selected biochemical parameters, these findings were not confirmed in multivariable models. No significant associations were observed between the analyzed cytokine polymorphisms and graft rejection, graft survival, patient survival, or clinically relevant markers of kidney graft function. Conclusions: The results suggest a possible, although not statistically significant, association between IL-10 rs1800896 and tacrolimus exposure, as assessed by the C/D ratio. This observation should be considered preliminary and interpreted with caution. The lack of CYP3A5 genotyping and functional assessment of IL-10 activity, inflammation, and CYP3A-dependent metabolism further limits the interpretation of this potential association. Larger prospective studies with comprehensive pharmacogenetic and functional characterization are needed to determine whether IL-10 rs1800896 contributes to interindividual variability in tacrolimus exposure and whether it may have potential applications in individualized immunosuppressive therapy. Full article
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