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Shriya A, Soni H, Sood G, Kumar N, Jamir I, Gupta A, Subramaniyam R, Lohia P, Wadhawan M, Chaudhary A. Sublingual Administration of Tacrolimus is Safe and Provides Similar Drug Exposure to Per-oral Route in Liver Transplant Recipients During Early Postoperative Period-A Large, Retrospective, Observational Study. J Clin Exp Hepatol 2025; 15:102422. [PMID: 39583914 PMCID: PMC11583714 DOI: 10.1016/j.jceh.2024.102422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Accepted: 10/05/2024] [Indexed: 11/26/2024] Open
Abstract
Background/Aims Per-oral (PO) administration of tacrolimus (TAC) results in inadequate trough levels in the early postoperative period in liver-transplant (LT) recipients who undergo Roux-en-Y hepaticojejunostomy for biliary reconstruction. Sublingual administration (SL) of tacrolimus provides an alternative route in such patients.The objectives of this study were to assess the feasibility and safety of SL tacrolimus in adult LT-recipients in the early postoperative period and to compare therapeutic efficacy of SL administration of tacrolimus versus PO route. Methods single-center, retrospective, observational study carried out in adult living donor liver transplant (LDLT) recipients between January 2022 and December 2022. Recipients who underwent Roux-en-Y hepaticojejunostomy for biliary reconstruction received tacrolimus through the SL route till postoperative day (POD) 5 as they were kept nil per oral constituted the study group while recipients who underwent duct-to-duct (D-D) anastomosis for biliary reconstruction were allowed orally from POD1 and received PO-tacrolimus were chosen as controls. The feasibility and safety of SL-tacrolimus were assessed in terms of patient acceptance, need to discontinue SL-tacrolimus, incidence of local adverse effects, and systemic adverse events like neurotoxicity and nephrotoxicity. Therapeutic efficacy was evaluated by comparing median trough levels (TAC level) achieved and incidence of graft rejection between two groups. Results Two hundred twelve patients underwent LT during the study period, of which 125 were included (58 in the SL-group and 67 in PO-group). Both groups had comparable baseline characteristics. In the SL-group, all patients tolerated SL-Tacrolimus well and no local adverse events were observed. Patients with SL-Tacrolimus administration achieved a higher median TAC level (ng/ml) vs. PO route (5.85 vs. 5 (P = 0.06)) despite receiving similar median cumulative tacrolimus dose before assessing TAC-level. Fifty percent of patients achieved TAC level ≥6 ng/ml in SL-group vs. 35.8% in PO-group (P = 0.14). The incidence of neurotoxicity, nephrotoxicity, and graft rejection during hospital stay were similar in both the groups (P = 0.56, 0.82, and 0.28, respectively). Conclusion SL-tacrolimus is safe and provides similar trough levels to PO-tacrolimus and may be considered as a viable alternative whenever inadequate TAC levels are anticipated through the per-oral route.
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Affiliation(s)
- Aditya Shriya
- Department of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, BLK MAX Super Specialty Hospital, New Delhi, India
| | - Hitesh Soni
- Department of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, BLK MAX Super Specialty Hospital, New Delhi, India
| | - Gaurav Sood
- Department of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, BLK MAX Super Specialty Hospital, New Delhi, India
| | - Niteen Kumar
- Department of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, BLK MAX Super Specialty Hospital, New Delhi, India
| | - Imtiakum Jamir
- Department of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, BLK MAX Super Specialty Hospital, New Delhi, India
| | - Anish Gupta
- Department of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, BLK MAX Super Specialty Hospital, New Delhi, India
| | - Rekha Subramaniyam
- Department of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, BLK MAX Super Specialty Hospital, New Delhi, India
| | - Pankaj Lohia
- Department of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, BLK MAX Super Specialty Hospital, New Delhi, India
| | - Manav Wadhawan
- Department of Gastroenterology and Hepatology, BLK-Max Super Speciality Hospital, New Delhi, India
| | - Abhideep Chaudhary
- Department of Hepato-Pancreato-Biliary Surgery and Liver Transplantation, BLK MAX Super Specialty Hospital, New Delhi, India
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Andishgar A, Bazmi S, Lankarani KB, Taghavi SA, Imanieh MH, Sivandzadeh G, Saeian S, Dadashpour N, Shamsaeefar A, Ravankhah M, Deylami HN, Tabrizi R, Imanieh MH. Comparison of time-to-event machine learning models in predicting biliary complication and mortality rate in liver transplant patients. Sci Rep 2025; 15:4768. [PMID: 39922959 PMCID: PMC11807176 DOI: 10.1038/s41598-025-89570-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Accepted: 02/06/2025] [Indexed: 02/10/2025] Open
Abstract
Post-Liver transplantation (LT) survival rates stagnate, with biliary complications (BC) as a major cause of death. We analyzed longitudinal data with a median 19-month follow-up. BC was diagnosed with ultrasounds and MRCP. Missing data was imputed using mean and median. Data preprocessing involved feature scaling and one-hot encoding. Survival analysis used filter (Cox-P, Cox-c) and embedded (RSF, LASSO) feature selection methods. Seven survival machine learning algorithms were used: LASSO, Ridge, RSF, E-NET, GBS, C-GBS, and FS-SVM. Model development employed 5-fold cross-validation, random oversampling, and hyperparameter tuning. Random oversampling addressed data imbalance. Optimal hyperparameters were determined based on average C-index. Features importance was assessed using standardized regression coefficients and permutation importance for top models. Stability was evaluated using 5-fold cross-validation standard deviation. Finally, 1799 observations with 40 outcome predictors were included. RSF with Ridge achieved the highest performance (C-index: 0.699) for BC prediction, while RSF with RSF had the highest performance (C-index: 0.784) for mortality prediction. Top BC predictors were LT graft types, IBD in recipients, recipient's BMI, recipient's history of PVT, and previous LT history. For mortality, they were post-transplant AST, creatinine, recipient's age, post-transplant ALT, and tacrolimus consumption. We identified BC and mortality risk factors, improving decision-making and outcomes.
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Affiliation(s)
- Aref Andishgar
- USERN Office, Fasa University of Medical Sciences, Fasa, Iran
| | - Sina Bazmi
- USERN Office, Fasa University of Medical Sciences, Fasa, Iran
| | - Kamran B Lankarani
- Health Policy Research Center, Institute of Heath, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Seyed Alireza Taghavi
- Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, 9th Floor, Mohammad Rasoul Allah Research Tower, Khalili St, 7193635899, Shiraz, Iran
| | - Mohammad Hadi Imanieh
- Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, 9th Floor, Mohammad Rasoul Allah Research Tower, Khalili St, 7193635899, Shiraz, Iran
| | - Gholamreza Sivandzadeh
- Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, 9th Floor, Mohammad Rasoul Allah Research Tower, Khalili St, 7193635899, Shiraz, Iran
| | - Samira Saeian
- Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, 9th Floor, Mohammad Rasoul Allah Research Tower, Khalili St, 7193635899, Shiraz, Iran
| | - Nazanin Dadashpour
- Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, 9th Floor, Mohammad Rasoul Allah Research Tower, Khalili St, 7193635899, Shiraz, Iran
| | - Alireza Shamsaeefar
- Abu Ali Sina Organ Transplant Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mahdi Ravankhah
- Student Research Committee, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Reza Tabrizi
- Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, 74616-86688, Iran.
- Clinical Research Development Unit of Vali Asr Hospital, Fasa University of Medical Science, Fasa, Iran.
| | - Mohammad Hossein Imanieh
- Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, 9th Floor, Mohammad Rasoul Allah Research Tower, Khalili St, 7193635899, Shiraz, Iran.
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Marquet P. Getting Tacrolimus Dosing Right. Ther Drug Monit 2025; 47:41-48. [PMID: 39357034 DOI: 10.1097/ftd.0000000000001266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Accepted: 08/23/2024] [Indexed: 10/04/2024]
Abstract
ABSTRACT Tacrolimus (TAC) dosing is typically guided by the trough concentration (C0). Yet, significant relationships between TAC C0 and clinical outcomes have seldom been reported or only with adverse events. Large retrospective studies found a moderate correlation between TAC C0 and the area under the curve (AUC), where, for any given C0 value, the AUC varied 3- to 4-fold between patients (and vice versa). However, no randomized controlled trial evaluating the dose adjustment based on TAC AUC has been conducted yet. A few observational studies have shown that the AUC is associated with efficacy and, to a lesser extent, adverse effects. Other studies showed the feasibility of reaching predefined target ranges and reducing underexposure and overexposure. TAC AUC 0-12 h is now most often assessed using Bayesian estimation, but machine learning is a promising approach. Microsampling devices are well accepted by patients and represent a valuable alternative to venous blood sample collection during hospital visits, especially when a limited sampling strategy is required. As AUC monitoring cannot be proposed very frequently, C0 monitoring has to be used in the interim, which has led to fluctuating doses in patients with an AUC/C0 ratio far from the population mean, because of different dose recommendations between the 2 biomarkers. We proposed estimating the individual AUC/C0 ratio and derived individual C0 targets to be used in between or as a replacement for AUC monitoring. Existing technology and evidence are now sufficient to propose AUC monitoring interspersed with individualized-C0 monitoring for all patients with kidney transplants while collecting real-world data to strengthen the evidence.
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Affiliation(s)
- Pierre Marquet
- Department of Pharmacology, Toxicology and Pharmacovigilance, CHU de Limoges, France ; and
- Pharmacology & Transplantation, UMR1248 Inserm, Université de Limoges, CHU de Limoges, France
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Monchaud C, Humeau A, Crépin S, Kawsarani L, Villeneuve C, Etienne I, Rerolle JP, Marquet P. Relationships Between Tacrolimus Exposure and Adverse Events in Renal Transplant Patients: The ExpoTac Study. Ther Drug Monit 2025; 47:152-160. [PMID: 39626094 DOI: 10.1097/ftd.0000000000001287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 10/24/2024] [Indexed: 01/11/2025]
Abstract
ABSTRACT In transplantation, the association of tacrolimus exposure with efficacy is better known than with adverse effects. The ExpoTac study explored the relationships between tacrolimus exposure and adverse events (AEs) in kidney transplant patients who benefited from at least 3 measurements of tacrolimus area under the curve (AUC) within 2 years of transplantation. The relationships between tacrolimus AUC, trough concentration C 0 , peak concentration C max , and AEs were explored using univariate analysis and Cox models in 386 patients (1281 sets of exposure biomarkers). Headaches and renal impairment potentially induced by tacrolimus were associated with significantly lower mean dose-standardized exposure biomarkers and a higher proportion of C max values above the median. Patients with tremor displayed significantly higher mean AUC 0-24 (343 ± 79 versus 308 ± 63 hours·mcg/L, P = 0.041). Cox analysis revealed a significant association between (1) the time to the first headache report and mean C max , mean AUC 0-24 , and the proportion of C max values above the median (hazard ratios [95% confidence interval] = 0.237 [0.007-0.538]; 7.499 [1.508-29.713]; 5.055 [1.577-17.137]) and (2) the time to first renal impairment report and the proportion of C 0 values above the median (0.401 [0.098-0.681]). Refining AUC, C max , and C 0 upper limits would help to refine tacrolimus therapeutic ranges and limit the risks of AEs after kidney transplantation.
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Affiliation(s)
- Caroline Monchaud
- Service de Pharmacologie, toxicologie et pharmacovigilance, CHU Limoges, Limoges, France
- INSERM UMR-1248 Pharmacologie et Transplantation, Université Limoges, Limoges, France
- FHU SUPORT, Limoges, France
| | - Antoine Humeau
- INSERM UMR-1248 Pharmacologie et Transplantation, Université Limoges, Limoges, France
- FHU SUPORT, Limoges, France
| | - Sabrina Crépin
- INSERM UMR-1248 Pharmacologie et Transplantation, Université Limoges, Limoges, France
- FHU SUPORT, Limoges, France
- Unité de Vigilance des Essais Cliniques, Service de Pharmacologie, Toxicologie et Pharmacovigilance, CHU Limoges, Limoges, France
| | - Lama Kawsarani
- Service de Pharmacologie, toxicologie et pharmacovigilance, CHU Limoges, Limoges, France
| | - Claire Villeneuve
- INSERM UMR-1248 Pharmacologie et Transplantation, Université Limoges, Limoges, France
- FHU SUPORT, Limoges, France
- Unité de Vigilance des Essais Cliniques, Service de Pharmacologie, Toxicologie et Pharmacovigilance, CHU Limoges, Limoges, France
| | - Isabelle Etienne
- Service de Néphrologie - Hémodialyse - Transplantation, CHU Rouen, Rouen, France ; and
| | - Jean-Philippe Rerolle
- INSERM UMR-1248 Pharmacologie et Transplantation, Université Limoges, Limoges, France
- FHU SUPORT, Limoges, France
- Service de Néphrologie, Dialyse et Transplantation, CHU Limoges, France
| | - Pierre Marquet
- Service de Pharmacologie, toxicologie et pharmacovigilance, CHU Limoges, Limoges, France
- INSERM UMR-1248 Pharmacologie et Transplantation, Université Limoges, Limoges, France
- FHU SUPORT, Limoges, France
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Servais A, Zacchia M, Dehoux L, Shroff R, Brassier A, Taurisano R, Kölker S, Oh J, Ariceta G, Stojanovic J, Hörster F, Strologo D, Spada M, Schiff M, Dionisi-Vici C. Clinical Practice Recommendations on Kidney Management in Methylmalonic Acidemia: an Expert Consensus Statement From ERKNet and MetabERN. Kidney Int Rep 2024; 9:3362-3374. [PMID: 39698355 PMCID: PMC11652068 DOI: 10.1016/j.ekir.2024.09.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 08/28/2024] [Accepted: 09/02/2024] [Indexed: 12/20/2024] Open
Abstract
Methylmalonic acidemias (MMAs) are rare inherited metabolic diseases with multiorgan involvement. Chronic kidney disease (CKD) is a common complication, leading to kidney failure, dialysis, and kidney transplantation (KT). The objective of these guidelines was to develop clinical practice recommendations focusing on specific aspects of the kidney management of this disease. Development of these clinical practice recommendations is an initiative of the European Reference Network for Rare Kidney Diseases in collaboration with the European Reference Network for Hereditary Metabolic Disorders and included pediatric and adult nephrologists, metabolic specialists, as well as liver and kidney transplant specialists. CKD has become a significant clinical issue that requires specific follow-up in both pediatric and adult departments. Creatinine-based formulae significantly overestimate kidney function and the estimation of estimated glomerular filtration rate (eGFR) is more accurate using cystatin C. Besides usual kidney indications, acute dialysis may be required in emergency in case of acute metabolic decompensation to clear metabolic toxins. Long-term dialysis may be initiated for clearance of toxic metabolites. Long hours on hemodialysis (HD) and/or daily dialysis are required. The indications for transplantation in MMA are a high rate of metabolic decompensations, a high burden of disease and difficult metabolic control. Transplantation is also indicated in case of long-term complications. Combined liver-kidney transplantation (LKT) should be preferred in patients with MMA with CKD. Possible calcineurin inhibitors (CNIs) induced neurotoxicity was described in patients with MMA requiring immunosuppressive treatment monitoring and adaptation. Overall, 13 statements were produced to provide guidance on the management of CKD, dialysis, and transplantation in pediatric and adult patients with MMA.
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Affiliation(s)
- Aude Servais
- Nephrology and Transplantation Department, Inherited Kidney Diseases Reference Center, Necker-Enfants Malades University Hospital, Assistance Publique Hôpitaux de Paris, Inserm U1163, Imagine Institute, Université de Paris, Paris, France
| | - Miriam Zacchia
- Department of Medical and Translational Sciences, University of Campania, Luigi Vanvitelli, Naples, Italy
| | - Laurène Dehoux
- Pediatric Nephrology Department, Necker-Enfants Malades University Hospital, Assistance Publique Hôpitaux de Paris, Paris, France
| | - Rukshana Shroff
- Institute of Child Health University College London, Great Ormond Street Hospital, NHS Foundation Trust, London, UK
| | - Anais Brassier
- Inherited Metabolic Diseases Reference Center, Necker-Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris Cité, Paris, France
| | - Roberta Taurisano
- Division of Metabolic Diseases and Hepatology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Stefan Kölker
- Division of Pediatric Neurology and Metabolic Medicine, Center for Pediatric and Adolescent Medicine, Heidelberg University, Medical Faculty, European Network for Hereditary Metabolic Disorders, Heidelberg, Germany
| | - Jun Oh
- University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Gema Ariceta
- Department of Pediatric Nephrology, Hospital Vall d'Hebron, Universitat Autonoma Barcelona, Barcelona, Spain
| | - Jelena Stojanovic
- Institute of Child Health University College London, Great Ormond Street Hospital, NHS Foundation Trust, London, UK
| | - Friederike Hörster
- Division of Pediatric Neurology and Metabolic Medicine, Center for Pediatric and Adolescent Medicine, Heidelberg University, Medical Faculty, European Network for Hereditary Metabolic Disorders, Heidelberg, Germany
| | - Dello Strologo
- Nephrology department, Bambino Gesù Children's Hospital IRCCS, Rome, Italy
| | - Marco Spada
- Division of Hepatobiliopancreatic Surgery, Liver and Kidney Transplantation; Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Manuel Schiff
- Inherited Metabolic Diseases Reference Center, Necker-Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, Université Paris Cité, Paris, France
| | - Carlo Dionisi-Vici
- Division of Metabolic Diseases and Hepatology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
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Berber M, Penton D. Calcineurin inhibitors and the renin-angiotensin-aldosterone system. Acta Physiol (Oxf) 2024; 240:e14248. [PMID: 39460458 DOI: 10.1111/apha.14248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Revised: 10/07/2024] [Accepted: 10/11/2024] [Indexed: 10/28/2024]
Abstract
Calcineurin inhibitors (CnIs) are effective immunosuppressants with decades of accumulated experience in treating immune disorders and, most notably, solid organ transplantation. While CnIs have significantly increased graft survival and transformed the patient standard of care, their use has been overshadowed by a number of undesired side effects. For instance, CnI-associated nephrotoxicity has been reported since early studies and remains a major therapeutic concern. The occurrence of several ion imbalances alongside hypertension was also noted early on, indicating the involvement of the renin-angiotensin-aldosterone system (RAAS) in CnI-mediated toxicity. However, the literature in this field is crowded with conflicting reports from clinical trials as well as studies using animal and invitro models. With this review, we aim to provide a structured and updated overview of the physiological and pathophysiological evidence supporting the involvement of the classical RAAS in CnI-associated toxicity.
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Affiliation(s)
- Mesut Berber
- Department of Pediatrics, Harvard Medical School and Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, USA
| | - David Penton
- Electrophysiology Facility, University of Zurich, Zurich, Switzerland
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Alghanem A, Joharji H, Garaween N, Alenazi H, Alsaleh NA, Broering D, Alshagrani M, Alhassan F, Albassam AA, Alsultan A, Alsmari A. A retrospective analysis of tacrolimus pharmacokinetic in Saudi paediatric patients in early post-liver transplantation period. Pediatr Neonatol 2024:S1875-9572(24)00201-8. [PMID: 39643483 DOI: 10.1016/j.pedneo.2024.11.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2024] [Revised: 10/20/2024] [Accepted: 11/06/2024] [Indexed: 12/09/2024] Open
Abstract
BACKGROUND Tacrolimus is an essential immunosuppressive medication in paediatric patients' post-liver transplantation. Achieving tacrolimus target concentration in early post-transplantation is crucial to minimise the risk of acute rejection; however, this is challenging due to inter- and intra-patient variability in tacrolimus metabolism and clearance. Therefore, our study aims to describe tacrolimus trough concentration variability and pharmacokinetics in paediatric post-liver transplantation during the first two weeks post-transplantation. METHOD This retrospective multicentre observational study included paediatric patients post-liver transplantation. Post-operative data was collected within the initial 14 days using electronic health records, including daily tacrolimus doses, measured trough concentrations, graft data, surgical data, and documented acute rejection. Pharmacokinetic analysis was completed using the Monolix software. We used the empirical Bayesian estimates of clearance and volume of distribution for covariate testing to assess possible correlations. We performed a stepwise regression analysis (alpha = 0.05). RESULTS Ninety-one paediatric patients were included in the study, with a mean age of 4.1 years (SD = 4.6). The mean graft-to-recipient weight ratio (GRWR) was 3% (SD = 6). The vast majority of the patients received the liver from living donors (n = 84, 92.3%). The average time needed to reach therapeutic concentration was 4.6 (SD = 2.8) days. The initial clearance (Clini) was very low at baseline (0.012 L/h), then increased dramatically to 9.84 L/h at 14 days post-transplantation. The clearance appeared to be time-dependent, and the time needed to reach 50% of maximum clearance was five days post-transplantation. The covariates that significantly affected clearance included bodyweight and aspartate transaminase, while the only significant covariate for volume of distribution was bodyweight. CONCLUSION Tacrolimus is a drug with high intra- and interindividual variability, making dosing challenging in the paediatric liver transplantation population. Prospective studies with more intensive sampling are needed to address the time-dependent changes in clearance, which will aid in establishing the optimal dosing regimens in this population.
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Affiliation(s)
- Ashjan Alghanem
- Pharmaceutical Care Division, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Hala Joharji
- Pharmaceutical Care Division, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia; College of Pharmacy, Alfaisal University, Riyadh, Saudi Arabia
| | | | - Huda Alenazi
- Pharmaceutical Care Department, King Abdulaziz Medical City, Riyadh, Saudi Arabia
| | - Nada A Alsaleh
- Department of Pharmacy Practice, College of Pharmacy, Princess Nourah Bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia.
| | - Dieter Broering
- Liver and SB Transplant and Hepatobiliary-Pancreatic Surgery, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Mohammed Alshagrani
- Liver and SB Transplant and Hepatobiliary-Pancreatic Surgery, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia; College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Fatimah Alhassan
- Pharmaceutical Care Department, King Abdulaziz Medical City, Riyadh, Saudi Arabia
| | - Ahmed A Albassam
- Department of Clinical Pharmacy, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al- Kharj, Saudi Arabia
| | - Abdullah Alsultan
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Abeer Alsmari
- Pharmaceutical Care Department, King Abdulaziz Medical City, Riyadh, Saudi Arabia; College of Pharmacy, King Saud Bin Abdulaziz University for Health Science, Riyadh, Saudi Arabia; King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
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8
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Chimura T, Manabe T. Ca2+-PP2B-PSD-95 axis: A novel regulatory mechanism of the phosphorylation state of Serine 295 of PSD-95. PLoS One 2024; 19:e0313441. [PMID: 39509447 PMCID: PMC11542788 DOI: 10.1371/journal.pone.0313441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 10/23/2024] [Indexed: 11/15/2024] Open
Abstract
The phosphorylation state of PSD-95 at Serine 295 (Ser295) is important for the regulation of synaptic plasticity. Although the activation of NMDA receptors (NMDARs), which initiates an intracellular calcium signaling cascade, decreases phosphorylated Ser295 (pS295) of PSD-95, the molecular mechanisms are not fully understood. We found that the calcium-activated protein phosphatase PP2B dephosphorylated pS295 not only in basal conditions but also in NMDAR-activated conditions in cultured neurons. The biochemical assay also revealed the dephosphorylation of pS295 by PP2B, consistently supporting the results obtained using neurons. The newly identified calcium signaling cascade "Ca2+-PP2B-PSD-95 axis" would play an important role in the molecular mechanism for NMDA receptor-dependent plasticity.
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Affiliation(s)
- Takahiko Chimura
- Department of Basic Medical Sciences, Institute of Medical Science, Division of Neuronal Network, University of Tokyo, Tokyo, Japan
| | - Toshiya Manabe
- Department of Basic Medical Sciences, Institute of Medical Science, Division of Neuronal Network, University of Tokyo, Tokyo, Japan
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9
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Jan MY, Patidar KR, Ghabril MS, Kubal CA. Optimization and Protection of Kidney Health in Liver Transplant Recipients: Intra- and Postoperative Approaches. Transplantation 2024:00007890-990000000-00916. [PMID: 39439013 DOI: 10.1097/tp.0000000000005252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2024]
Abstract
Postoperative acute kidney injury after liver transplant (LT) has long-term implications for kidney health. LT recipients are at risk of acute kidney injury due to a number of factors related to the donor liver, intraoperative factors including surgical technique, as well as recipient factors, such as pre-LT kidney function and postoperative complications. This review discusses these factors in detail and their impact on posttransplant kidney function. Long-term risk factors such as calcineurin inhibitors have also been discussed. Additionally, the impact of liver allocation policies on pre- and post-LT kidney health is discussed.
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Affiliation(s)
- Muhammad Y Jan
- Division of Transplant Nephrology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Kavish R Patidar
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX
| | - Marwan S Ghabril
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Chandrashekhar A Kubal
- Division of Transplant Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN
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10
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Attachaipanich T, Chattipakorn SC, Chattipakorn N. Cardiovascular toxicities by calcineurin inhibitors: Cellular mechanisms behind clinical manifestations. Acta Physiol (Oxf) 2024; 240:e14199. [PMID: 38984711 DOI: 10.1111/apha.14199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Revised: 06/19/2024] [Accepted: 06/25/2024] [Indexed: 07/11/2024]
Abstract
Calcineurin inhibitors (CNI), including cyclosporine A (CsA) and tacrolimus (TAC), are cornerstones of immunosuppressive therapy in solid organ transplant recipients. While extensively recognized for their capacity to induce nephrotoxicity, hypertension, and dyslipidemia, emerging reports suggest potential direct cardiovascular toxicities associated with CNI. Evidence from both in vitro and in vivo studies has demonstrated direct cardiotoxic impact of CNI, manifesting itself as induction of cardiomyocyte apoptosis, enhanced oxidative stress, inflammatory cell infiltration, and cardiac fibrosis. CNI enhances cellular apoptosis through CaSR via activation of the p38 MAPK pathway and deactivation of the ERK pathway, and enhancement of miR-377 axis. Although CNI could attenuate cardiac hypertrophy in certain animal models, CNI concurrently impaired systolic function, enhanced cardiac fibrosis, and increased the risk of heart failure. Evidence from in vivo studies demonstrated that CNI prolong the duration of action potentials through a decrease in potassium current. CNI also exerted direct effects on endothelial cell injury, inducing apoptosis and enhancing oxidative stress. CNI may induce vascular inflammation through TLR4 via MyD88 and TRIF pathways. In addition, CNI affects vascular function by impairing endothelial-dependent vasodilation and promoting vasoconstriction. Clinical studies in transplant patients also revealed an increased incidence of cardiac remodeling. However, the evidence is constrained by the limited number of participants and potential confounding factors. Several studies indicate differing cardiovascular toxicity profiles between CsA and TAC, and these could be potentially due to their different interactions with calcineurin subunits and calcineurin-independent effects. Further studies are needed to clarify these mechanisms to improve cardiovascular outcomes for transplant patients with CNI.
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Affiliation(s)
- Tanawat Attachaipanich
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand
| | - Siriporn C Chattipakorn
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand
| | - Nipon Chattipakorn
- Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
- Center of Excellence in Cardiac Electrophysiology Research, Chiang Mai University, Chiang Mai, Thailand
- Cardiac Electrophysiology Research Unit, Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
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11
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Maddur H, Wilson N, Patil P, Asrani S. Rejection in Liver Transplantation Recipients. J Clin Exp Hepatol 2024; 14:101363. [PMID: 38495462 PMCID: PMC10943490 DOI: 10.1016/j.jceh.2024.101363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 02/09/2024] [Indexed: 03/19/2024] Open
Abstract
Rejection following liver transplantation continues to impact transplant recipients although rates have decreased over time with advances in immunosuppression management. The diagnosis of rejection remains challenging with liver biopsy remaining the reference standard for diagnosis. Proper classification of rejection type and severity is imperative as this guides management and ultimately graft preservation. Future areas of promise include non-invasive testing for detection of rejection to reduce the morbidity associated with invasive testing and further advances in immunosuppression management to reduce toxicities associated with immunosuppression while minimizing rejection related morbidity.
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12
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Wang M, Zhou J, Niu Q, Wang H. Mechanism of tacrolimus in the treatment of lupus nephritis. Front Pharmacol 2024; 15:1331800. [PMID: 38774214 PMCID: PMC11106426 DOI: 10.3389/fphar.2024.1331800] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 04/19/2024] [Indexed: 05/24/2024] Open
Abstract
Systemic lupus erythematosus (SLE) is a complex autoimmune disorder, with more than half of the patients developing lupus nephritis (LN), which significantly contributes to chronic kidney disease (CKD) and end-stage renal disease (ESRD). The treatment of lupus nephritis has always been challenging. Tacrolimus (TAC), an effective immunosuppressant, has been increasingly used in the treatment of LN in recent years. This review aims to explore the mechanisms of action of tacrolimus in treating LN. Firstly, we briefly introduce the pharmacological properties of tacrolimus, including its role as a calcineurin (CaN) inhibitor, exerting immunosuppressive effects by inhibiting T cell activation and cytokine production. Subsequently, we focus on various other immunomodulatory mechanisms of tacrolimus in LN therapy, including its effects on T cells, B cells, and immune cells in kidney. Particularly, we emphasize tacrolimus' regulatory effect on inflammatory mediators and its importance in modulating the Th1/Th2 and Th17/Treg balance. Additionally, we review its effects on actin cytoskeleton, angiotensin II (Ang II)-specific vascular contraction, and P-glycoprotein activity, summarizing its impacts on non-immune mechanisms. Finally, we summarize the efficacy and safety of tacrolimus in clinical studies and trials. Although some studies have shown significant efficacy of tacrolimus in treating LN, its safety remains a challenge. We outline the potential adverse reactions of long-term tacrolimus use and provide suggestions on effectively monitoring and managing these adverse reactions in clinical practice. In general, tacrolimus, as a novel immunosuppressant, holds promising prospects for treating LN. Of course, further research is needed to better understand its therapeutic mechanisms and ensure its safety and efficacy in clinical practice.
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Affiliation(s)
| | | | | | - Hongyue Wang
- Department of Nephrology, The First Hospital of Jilin University, Changchun, China
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13
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Chandras A, Mendu DR, Kirchhoff DC. Effect of Extraction Procedure Substitution on Automated Tacrolimus, Sirolimus, and Cyclosporine Assays. J Appl Lab Med 2024; 9:573-578. [PMID: 38300648 DOI: 10.1093/jalm/jfad128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Accepted: 10/30/2023] [Indexed: 02/02/2024]
Abstract
BACKGROUND An erroneously high tacrolimus level was reported to a clinician. A root cause analysis investigation failed to determine the cause of the error. It was suspected that the incorrect preanalytical extraction reagent and procedure was used during testing; however, how this would affect the assayed drug concentration was unclear. Here we investigated the effect of the substitution of sirolimus, tacrolimus, and cyclosporine extraction reagents on assayed drug concentration. METHODS Tacrolimus, sirolimus, and cyclosporine concentration were measured on the Abbott Architect i2000 analyzer. Each assay requires a preanalytical extraction step, with a distinct reagent. We investigated the effect of the substitution of the extraction reagents and procedure between the 3 assays on the measured drug concentration. Two experiments were performed, one on samples of known drug concentration and one on samples with no drug present. RESULTS Substituting cyclosporine and sirolimus extraction procedures increased assayed tacrolimus concentrations from 5.6 to 8.47 (+51.25%) and 8.13 (+45.18%) ng/mL, respectively. Extraction procedure substitutions decreased assayed sirolimus from 13.63 to 4.60 (-66.25%) and 8.07 (-40.79%) ng/mL for cyclosporine and tacrolimus. Cyclosporine concentration increased from 274.60 to 391.30 (+42.50%) ng/mL using sirolimus extraction reagents and to 757.30 (+175.78%) ng/mL using tacrolimus extraction reagents. Cross-reactivity was observed between the tacrolimus assay and sirolimus and cyclosporine extraction reagents. CONCLUSIONS Significant changes, both positive and negative, are observed in assayed drug concentration when incorrect extraction procedures are used in the Abbott i2000 tacrolimus, sirolimus, and cyclosporine assays. Preanalytic extraction procedures should be investigated when performing root cause analysis for erroneous therapeutic drug values.
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Affiliation(s)
- Athanasia Chandras
- Department of Pathology, Molecular & Cell Based Medicine, Mount Sinai Hospital, New York, NY, United States
| | - Damodara R Mendu
- Department of Pathology, Molecular & Cell Based Medicine, Mount Sinai Hospital, New York, NY, United States
| | - Daniel C Kirchhoff
- Department of Pathology, Molecular & Cell Based Medicine, Mount Sinai Hospital, New York, NY, United States
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14
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Poudel S, Gupta S, Saigal S. Basics and Art of Immunosuppression in Liver Transplantation. J Clin Exp Hepatol 2024; 14:101345. [PMID: 38450290 PMCID: PMC10912712 DOI: 10.1016/j.jceh.2024.101345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Accepted: 01/09/2024] [Indexed: 03/08/2024] Open
Abstract
Liver transplantation is one of the most challenging areas in the medical field. Despite that, it has already been established as a standard treatment option, especially in decompensated cirrhosis and selected cases of hepatocellular carcinoma and acute liver failure. Complications due to graft rejection, including mortality and morbidity, have greatly improved over time due to better immunosuppressive agents and management protocols. Currently, immunosuppression in liver transplant patients makes use of the best possible combinations of effective agents to achieve optimal immunosuppression for long-term graft survival. Induction agents are no longer used routinely, and the aim is to provide minimal immunosuppression in the maintenance phase. Currently available immunosuppressive agents are mainly classified as biological and pharmacological agents. Though the protocols may vary among the centers and over time, the basics of effective use usually remain similar. Most protocols use the combination of multiple agents with different mechanisms of action to reduce the dose and minimize the side effects. Along with the improvement in operative and perioperative techniques, this art of immunosuppression has contributed to the recent progress made in the outcomes of liver transplants. In this review, we will discuss the various types of immunosuppressive agents currently in use, the different protocols of immunosuppression used, and the art of optimal use for achieving maximum immunosuppression without increasing toxicity. We will also discuss the practical aspects of various immunosuppression regimens, including drug monitoring, and briefly discuss the concepts of immunosuppression minimization and withdrawal.
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Affiliation(s)
- Shekhar Poudel
- Fellow Transplant Hepatology, Centre for Liver and Biliary Sciences, Max Super Specialty Hospital, Saket, New Delhi, India
| | - Subhash Gupta
- Liver Transplant and Gastrointestinal Surgery, Centre for Liver and Biliary Sciences, Max Super Speciality Hospital, Saket, New Delhi, India
| | - Sanjiv Saigal
- Principal Director and Head, Transplant Hepatology, Centre for Liver and Biliary Sciences, Max Super Specialty Hospital, Saket, New Delhi, India
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15
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Kim DS, Yoon YI, Kim BK, Choudhury A, Kulkarni A, Park JY, Kim J, Sinn DH, Joo DJ, Choi Y, Lee JH, Choi HJ, Yoon KT, Yim SY, Park CS, Kim DG, Lee HW, Choi WM, Chon YE, Kang WH, Rhu J, Lee JG, Cho Y, Sung PS, Lee HA, Kim JH, Bae SH, Yang JM, Suh KS, Al Mahtab M, Tan SS, Abbas Z, Shresta A, Alam S, Arora A, Kumar A, Rathi P, Bhavani R, Panackel C, Lee KC, Li J, Yu ML, George J, Tanwandee T, Hsieh SY, Yong CC, Rela M, Lin HC, Omata M, Sarin SK. Asian Pacific Association for the Study of the Liver clinical practice guidelines on liver transplantation. Hepatol Int 2024; 18:299-383. [PMID: 38416312 DOI: 10.1007/s12072-023-10629-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 12/18/2023] [Indexed: 02/29/2024]
Abstract
Liver transplantation is a highly complex and challenging field of clinical practice. Although it was originally developed in western countries, it has been further advanced in Asian countries through the use of living donor liver transplantation. This method of transplantation is the only available option in many countries in the Asia-Pacific region due to the lack of deceased organ donation. As a result of this clinical situation, there is a growing need for guidelines that are specific to the Asia-Pacific region. These guidelines provide comprehensive recommendations for evidence-based management throughout the entire process of liver transplantation, covering both deceased and living donor liver transplantation. In addition, the development of these guidelines has been a collaborative effort between medical professionals from various countries in the region. This has allowed for the inclusion of diverse perspectives and experiences, leading to a more comprehensive and effective set of guidelines.
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Affiliation(s)
- Dong-Sik Kim
- Department of Surgery, Korea University College of Medicine, Seoul, Republic of Korea
| | - Young-In Yoon
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | | | | | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jongman Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Dong Hyun Sinn
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Dong Jin Joo
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - YoungRok Choi
- Department of Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jeong-Hoon Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Ho Joong Choi
- Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Ki Tae Yoon
- Department of Internal Medicine, Pusan National University College of Medicine, Yangsan, Republic of Korea
| | - Sun Young Yim
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Cheon-Soo Park
- Department of Surgery, Eunpyeong St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Deok-Gie Kim
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hae Won Lee
- Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea
| | - Won-Mook Choi
- Department of Gastroenterology, Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Young Eun Chon
- Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Republic of Korea
| | - Woo-Hyoung Kang
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jinsoo Rhu
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jae Geun Lee
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yuri Cho
- Center for Liver and Pancreatobiliary Cancer, National Cancer Center, Ilsan, Republic of Korea
| | - Pil Soo Sung
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Han Ah Lee
- Department of Internal Medicine, Ewha Womans University, Seoul, Republic of Korea
| | - Ji Hoon Kim
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea
| | - Si Hyun Bae
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jin Mo Yang
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
| | - Kyung-Suk Suh
- Department of Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea.
| | - Mamun Al Mahtab
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Soek Siam Tan
- Department of Medicine, Hospital Selayang, Batu Caves, Selangor, Malaysia
| | - Zaigham Abbas
- Sindh Institute of Urology and Transplantation, Karachi, Pakistan
| | - Ananta Shresta
- Department of Hepatology, Alka Hospital, Lalitpur, Nepal
| | - Shahinul Alam
- Crescent Gastroliver and General Hospital, Dhaka, Bangladesh
| | - Anil Arora
- Department of Gastroenterology and Hepatology, Sir Ganga Ram Hospital New Delhi, New Delhi, India
| | - Ashish Kumar
- Department of Gastroenterology and Hepatology, Sir Ganga Ram Hospital New Delhi, New Delhi, India
| | - Pravin Rathi
- TN Medical College and BYL Nair Hospital, Mumbai, India
| | - Ruveena Bhavani
- University of Malaya Medical Centre, Petaling Jaya, Selangor, Malaysia
| | | | - Kuei Chuan Lee
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Jun Li
- College of Medicine, Zhejiang University, Hangzhou, China
| | - Ming-Lung Yu
- Department of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | | | | | | | | | | | - H C Lin
- Endoscopy Center for Diagnosis and Treatment, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Masao Omata
- Department of Gastroenterology, Yamanashi Central Hospital, Yamanashi, Japan
- University of Tokyo, Bunkyo City, Japan
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16
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Li JJ, Chen L, Zhao Y, Yang XQ, Hu FB, Wang L. Data mining and safety analysis of traditional immunosuppressive drugs: a pharmacovigilance investigation based on the FAERS database. Expert Opin Drug Saf 2024; 23:513-525. [PMID: 38533933 DOI: 10.1080/14740338.2024.2327503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 10/13/2023] [Indexed: 03/28/2024]
Abstract
OBJECTIVE The purpose of this study aimed to explore the new and serious adverse events(AEs) of Tacrolimus(FK506), cyclosporine(CsA), azathioprine(AZA), mycophenolate mofetil(MMF), cyclophosphamide(CTX) and methotrexate(MTX), which have not been concerned. METHODS The FAERS data from January 2016 and December 2022 were selected for disproportionality analysis to discover the potential risks of traditional immunosuppressive drugs. RESULTS Compared with CsA, FK506 has more frequent transplant rejection, and is more related to renal impairment, COVID-19, cytomegalovirus infection and aspergillus infection. However, CsA has a high infection-related fatality rate. In addition, we also found some serious and rare AE in other drugs which were rarely reported in previous studies. For example, AZA is closely related to hepatosplenic T-cell lymphoma with high fatality rate and MTX is strongly related to hypofibrinogenemia. CONCLUSION The AEs report on this study confirmed that the results were basically consistent with the previous studies, but there were also some important safety signals that were inconsistent with or not mentioned in previous published studies. EXPERT OPINION The opinion section discusses some of the limitations and shortcomings, proposing the areas where more effort should be invested in order to improve the safety of immunosuppressive drugs.
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Affiliation(s)
- Juan-Juan Li
- Department of Pharmacy, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- Ministry of Education, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Chengdu, Sichuan, China
- Department of Pharmacy, Guangyuan Central Hospital, Guanyuan, Sichuan, China
| | - Li Chen
- Department of Pharmacy, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- Ministry of Education, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Chengdu, Sichuan, China
| | - Yang Zhao
- Department of Pharmacy, Guangyuan Central Hospital, Guanyuan, Sichuan, China
| | - Xue-Qin Yang
- Department of Pharmacy, Guangyuan Central Hospital, Guanyuan, Sichuan, China
| | - Fa-Bin Hu
- Department of Pharmacy, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- Ministry of Education, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Chengdu, Sichuan, China
- Department of Pharmacy, Jinniu Maternity and Child Health Hospital of Chengdu, Chengdu, Sichuan, China
| | - Li Wang
- Department of Pharmacy, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
- Ministry of Education, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Chengdu, Sichuan, China
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17
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Dai A, Kim SJ. Systemic calcineurin inhibitors tacrolimus and voclosporin: A review of off-label dermatologic uses. J Am Acad Dermatol 2024; 90:358-367. [PMID: 37307993 DOI: 10.1016/j.jaad.2023.05.074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 05/08/2023] [Accepted: 05/18/2023] [Indexed: 06/14/2023]
Abstract
BACKGROUND Systemic calcineurin inhibitors, cyclosporine, tacrolimus, and voclosporin, have been utilized in various dermatologic conditions. Although there have been numerous off-label dermatologic indications with published guidelines for cyclosporine, there is no established strong consensus for tacrolimus and voclosporin. OBJECTIVE To conduct a review of off-label use of systemic tacrolimus and voclosporin in various dermatoses to better inform treatment methods. METHODS A literature search was conducted using PubMed and Google Scholar. Relevant clinical trials, observational studies, case series, and reports regarding off-label dermatologic uses of systemic tacrolimus and voclosporin were included. RESULTS Tacrolimus shows promise for numerous dermatologic conditions, including psoriasis, atopic dermatitis/eczema, pyoderma gangrenosum, chronic urticaria, and Behcet's disease. Randomized controlled trial data are only available for voclosporin in psoriasis, which showed efficacy but did not meet noninferiority to cyclosporine. LIMITATIONS Data were limited and extracted from published papers. Studies differed in methodology, and nonstandardized outcomes limited the conclusions drawn. CONCLUSIONS In comparison to cyclosporine, tacrolimus can be considered for treatment-refractory disease or in patients with cardiovascular risk factors or inflammatory bowel disease. Voclosporin has only been utilized in psoriasis currently, and clinical trials in psoriasis show voclosporin's efficacy. Voclosporin can be considered for patients with lupus nephritis.
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Affiliation(s)
- Annie Dai
- Department of Dermatology, Baylor College of Medicine, Houston, Texas
| | - Soo Jung Kim
- Department of Dermatology, Baylor College of Medicine, Houston, Texas.
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18
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Liu H, Sethi V, Li X, Xiao Y, Humar A. Liver Transplantation for Hepatocellular Carcinoma: A Narrative Review and A Glimpse into The Future. Semin Liver Dis 2024; 44:79-98. [PMID: 38211621 DOI: 10.1055/a-2242-7543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2024]
Abstract
Liver transplantation (LT) is a highly effective treatment for carefully selected patients with hepatocellular carcinoma (HCC). In this review, we explored the development of LT selection criteria and organ allocation policies, comparing original data to underscore their historical progression into the intricate task of quantitatively estimating pre- and post-LT survivals. We emphasized the role of biomarkers such as serum alpha-fetoprotein, Des-gamma-carboxy-prothrombin, circulating tumor cells, and circulating tumor DNA in predicting patient outcomes. Additionally, we examined the transplant-associated survival benefits and the difficulties in accurately calculating these benefits. We also reviewed recent advancements in targeted therapy and checkpoint inhibitors for advanced, inoperable HCC and projected their integration into LT for HCC. We further discussed the growing use of living donor liver transplants in the United States and compared its outcomes with those of deceased donor liver transplants. Furthermore, we examined the progress in machine perfusion techniques, which have shown potential in improving patient outcomes and enlarging the donor pool. These advancements present opportunities to enhance LT patient survivals, refine selection criteria, establish new priority metrics, develop innovative bridging and downstaging strategies, and formulate redesigned LT strategies for HCC treatments.
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Affiliation(s)
- Hao Liu
- Department of Surgery, Starzl Transplant Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Vrishketan Sethi
- Department of Surgery, Starzl Transplant Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Xingjie Li
- Division of Transplant Surgery, Department of Surgery, Mayo Clinic Arizona, Phoenix, Arizona
| | - Yao Xiao
- Division of Transplant Surgery and Transplant Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Abhinav Humar
- Department of Surgery, Starzl Transplant Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
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19
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Helmick RA, Eymard CM, Naik S, Eason JD, Nezakatgoo N, Nair S, Vanatta JM. A report of a prospective randomized trial of extended-release tacrolimus versus immediate release tacrolimus after liver transplantation with anti-thymocyte induction in a steroid free protocol. Clin Transplant 2024; 38:e15172. [PMID: 37897198 DOI: 10.1111/ctr.15172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 10/09/2023] [Accepted: 10/17/2023] [Indexed: 10/29/2023]
Abstract
PURPOSE Our study hypothesis was that once daily dosing of extended-release tacrolimus (XRT) would be a safe and effective immunosuppression (IS) with the potential to decrease adverse events (AEs) associated with immediate release tacrolimus (IRT) after liver transplantation (LT). METHODS All patients receiving LT at our center received rabbit anti-thymocyte globulin (RATG) induction therapy. Eligible patients were randomized in a 1:1 fashion to receive either XRT or IRT. Antimicrobial prophylaxis was the same between arms, and both groups received an antimetabolite for the first 6 months following LT. Patients were then followed at pre-determined study intervals for the following year after LT. We administered the RAND-36SF survey to assess patient's health-related quality of life at pre-determined intervals. All analysis was performed with an intention to treat basis. RESULTS We screened 194 consecutive patients and enrolled 110. Our control and study arms were well matched. Transplant characteristics were similar between groups. At all timepoints, both arms had similar serum creatinine and estimated glomerular filtration rate (eGFR), calculated by MDRD6 equation, with post-transplant GFRs between 60 and 70 mL/min/1.73 m2 . Tacrolimus trough levels were similar between arms. The XRT arm had fewer AEs (166) and fewer serious AEs (70) compared to IRT (201 and 99, respectively). AEs most commonly were renal, infectious, or gastrointestinal in nature. While not statistically significant, XRT was held temporarily (25 vs. 35 cases) or discontinued (3 vs. 11 cases) less frequently than IRT and had fewer instances of rejection (7 vs. 12 cases). CONCLUSION This analysis showed that XRT is safe and effective as de novo maintenance IS in a steroid-free protocol with RATG.
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Affiliation(s)
- Ryan A Helmick
- Methodist Transplant Institute, Methodist University Hospital, Memphis, Tennessee, USA
- Department of Surgery, Division of Transplantation, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Corey M Eymard
- Methodist Transplant Institute, Methodist University Hospital, Memphis, Tennessee, USA
- Department of Surgery, Division of Transplantation, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Surabhi Naik
- Department of Surgery, Division of Transplantation, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - James D Eason
- Department of Surgery, Division of Transplantation, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Nosratollah Nezakatgoo
- Methodist Transplant Institute, Methodist University Hospital, Memphis, Tennessee, USA
- Department of Surgery, Division of Transplantation, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Satheesh Nair
- Methodist Transplant Institute, Methodist University Hospital, Memphis, Tennessee, USA
- Department of Surgery, Division of Transplantation, University of Tennessee Health Science Center, Memphis, Tennessee, USA
| | - Jason M Vanatta
- Methodist Transplant Institute, Methodist University Hospital, Memphis, Tennessee, USA
- Department of Surgery, Division of Transplantation, University of Tennessee Health Science Center, Memphis, Tennessee, USA
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20
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Odenwald MA, Roth HF, Reticker A, Segovia M, Pillai A. Evolving challenges with long-term care of liver transplant recipients. Clin Transplant 2023; 37:e15085. [PMID: 37545440 DOI: 10.1111/ctr.15085] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Revised: 07/17/2023] [Accepted: 07/23/2023] [Indexed: 08/08/2023]
Abstract
The number of liver transplants (LT) performed worldwide continues to rise, and LT recipients are living longer post-transplant. This has led to an increasing number of LT recipients requiring lifelong care. Optimal care post-LT requires careful attention to both the allograft and systemic issues that are more common after organ transplantation. Common causes of allograft dysfunction include rejection, biliary complications, and primary disease recurrence. While immunosuppression prevents rejection and reduces incidences of some primary disease recurrence, it has detrimental systemic effects. Most commonly, these include increased incidences of metabolic syndrome, various malignancies, and infections. Therefore, it is of utmost importance to optimize immunosuppression regimens to prevent allograft dysfunction while also decreasing the risk of systemic complications. Institutional protocols to screen for systemic disease and heightened clinical suspicion also play an important role in providing optimal long-term post-LT care. In this review, we discuss these common complications of LT as well as unique considerations when caring for LT recipients in the years after transplant.
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Affiliation(s)
- Matthew A Odenwald
- Department of Medicine, Section of Gastroenterology, Hepatology, and Nutrition, University of Chicago Medicine, Chicago, USA
| | - Hannah F Roth
- Department of Medicine, Section of Gastroenterology, Hepatology, and Nutrition, University of Chicago Medicine, Chicago, USA
| | - Anesia Reticker
- Department of Pharmacy, University of Chicago Medicine, Chicago, USA
| | - Maria Segovia
- Department of Medicine, Section of Gastroenterology, Duke University School of Medicine, Durham, USA
| | - Anjana Pillai
- Department of Medicine, Section of Gastroenterology, Hepatology, and Nutrition, University of Chicago Medicine, Chicago, USA
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21
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Mathew JS, Philips CA. Drug Interactions and Safe Prescription Writing for Liver Transplant Recipients. J Clin Exp Hepatol 2023; 13:869-877. [PMID: 37693257 PMCID: PMC10483006 DOI: 10.1016/j.jceh.2023.03.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 03/28/2023] [Indexed: 09/12/2023] Open
Abstract
Immunosuppression optimization is central to graft function in liver transplant recipients. Post-transplantation patients develop new onset or worsening metabolic syndrome, are prone to atypical infections, and are at higher risk of developing cardiac and brain-related clinical events. In this context, liver transplant recipients are at risk of using multiple comedications alongside immunosuppressants. It is imperative for the transplant physician to understand the various drug-drug interactions that potentially reduce or promote toxicity of immunosuppression, as well as associated synergistic or antagonistic effects on extrahepatic organ systems. This comprehensive review discusses drug-drug interactions in liver transplant recipients and the impact and role of complementary and alternative medicines among individuals on immunosuppression.
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Affiliation(s)
- Johns S. Mathew
- Gastrointestinal, Hepatobiliary and Multi-organ Transplant Surgery, Center of Excellence in Gastrointestinal Sciences, Rajagiri Hospital, Aluva, Kerala 683112, India
| | - Cyriac A. Philips
- Clinical and Translational Hepatology & Monarch Liver Laboratory, The Liver Institute, Center for Excellence in Gastrointestinal Sciences, Rajagiri Hospital, Aluva, Kerala 683112, India
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22
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O’Leary JG, Farris AB, Gebel HM, Asrani SK, Askar M, Garcia V, Snipes GJ, Lo DJ, Knechtle SJ, Klintmalm GB, Demetris AJ. Detailed Analysis of Simultaneous Renal and Liver Allografts in the Presence of DSA. Transplant Direct 2023; 9:e1500. [PMID: 37456590 PMCID: PMC10348731 DOI: 10.1097/txd.0000000000001500] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 04/12/2023] [Accepted: 04/25/2023] [Indexed: 07/18/2023] Open
Abstract
Liver allografts protect renal allografts from the same donor from some, but not all, preformed donor specific alloantibodies (DSA). However, the precise mechanisms of protection and the potential for more subtle alterations/injuries within the grafts resulting from DSA interactions require further study. Methods We reevaluated allograft biopsies from simultaneous liver-kidney transplant recipients who had both allografts biopsied within 60 d of one another and within 30 d of DSA being positive in serum (positive: mean florescence intensity ≥5000). Routine histology, C4d staining, and specialized immunohistochemistry for Kupffer cells (KCs; CD163) and a C4d receptor immunoglobulin-like transcript-4 were carried out in 4 patients with 6 paired biopsies. Results Overt antibody-mediated rejection was found in 3 of 4 renal and liver allografts. One patient had biopsy-confirmed renal and liver allograft antibody-mediated rejection despite serum clearance of DSA. All biopsies showed KC hypertrophy (minimal: 1; mild: 2; moderate: 1; severe: 2) and cytoplasmic C4d KC staining was easily detected in 2 biopsies from 2 patients; minimal and negative in 2 biopsies each. Implications of which are discussed. Control 1-y protocol liver allograft biopsies from DSA- recipients showed neither KC hypertrophy nor KC C4d staining (n = 6). Conclusions Partial renal allograft protection by a liver allograft from the same donor may be partially mediated by phagocytosis/elimination of antibody and complement split products by KCs, as shown decades ago in controlled sensitized experimental animal experiments.
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Affiliation(s)
| | - Alton B. Farris
- Department of Pathology, Emory University Hospital, Atlanta, GA
| | - Howard M. Gebel
- Department of Pathology, Emory University Hospital, Atlanta, GA
| | - Sumeet K. Asrani
- Annette C. & Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas TX
| | - Medhat Askar
- Annette C. & Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas TX
| | - Vanessa Garcia
- Annette C. & Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas TX
| | - George J. Snipes
- Department of Pathology, Baylor University Medical Center, Dallas TX
| | - Denise J. Lo
- Department of Surgery, Duke University, Durham, NC
| | | | - Goran B. Klintmalm
- Annette C. & Harold C. Simmons Transplant Institute, Baylor University Medical Center, Dallas TX
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23
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Wu X, Tao M, Zhu L, Zhang T, Zhang M. Pathogenesis and current therapies for non-infectious uveitis. Clin Exp Med 2023; 23:1089-1106. [PMID: 36422739 PMCID: PMC10390404 DOI: 10.1007/s10238-022-00954-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 11/16/2022] [Indexed: 11/25/2022]
Abstract
Non-infectious uveitis (NIU) is a disorder with various etiologies and is characterized by eye inflammation, mainly affecting people of working age. An accurate diagnosis of NIU is crucial for appropriate therapy. The aim of therapy is to improve vision, relieve ocular inflammation, prevent relapse, and avoid treatment side effects. At present, corticosteroids are the mainstay of topical or systemic therapy. However, repeated injections are required for the treatment of chronic NIU. Recently, new drug delivery systems that may ensure intraocular delivery of therapeutic drug levels have been highlighted. Furthermore, with the development of immunosuppressants and biologics, specific therapies can be selected based on the needs of each patient. Immunosuppressants used in the treatment of NIU include calcineurin inhibitors and antimetabolites. However, systemic immunosuppressive therapy itself is associated with adverse effects due to the inhibition of immune function. In patients with refractory NIU or those who cannot tolerate corticosteroids and immunosuppressors, biologics have emerged as alternative treatments. Thus, to improve the prognosis of patients with NIU, NIU should be managed with different drugs according to the response to treatment and possible side effects.
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Affiliation(s)
- Xue Wu
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, 610041, China
- Save Sight Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, 2000, Australia
| | - Mengying Tao
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Ling Zhu
- Save Sight Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, 2000, Australia
| | - Ting Zhang
- Save Sight Institute, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, 2000, Australia
| | - Ming Zhang
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, 610041, China.
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24
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Thomson M, Lake JR. CAQ Corner: Immune-mediated complications. Liver Transpl 2023; 29:885-893. [PMID: 35748497 PMCID: PMC10344430 DOI: 10.1002/lt.26535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Revised: 06/04/2022] [Accepted: 06/14/2022] [Indexed: 01/12/2023]
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25
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Berber M, Leng S, Wengi A, Winter DV, Odermatt A, Beuschlein F, Loffing J, Breault DT, Penton D. Calcineurin regulates aldosterone production via dephosphorylation of NFATC4. JCI Insight 2023; 8:e157027. [PMID: 37310791 PMCID: PMC10443813 DOI: 10.1172/jci.insight.157027] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 06/08/2023] [Indexed: 06/15/2023] Open
Abstract
The mineralocorticoid aldosterone, secreted by the adrenal zona glomerulosa (ZG), is critical for life, maintaining ion homeostasis and blood pressure. Therapeutic inhibition of protein phosphatase 3 (calcineurin, Cn) results in inappropriately low plasma aldosterone levels despite concomitant hyperkalemia and hyperreninemia. We tested the hypothesis that Cn participates in the signal transduction pathway regulating aldosterone synthesis. Inhibition of Cn with tacrolimus abolished the potassium-stimulated (K+-stimulated) expression of aldosterone synthase, encoded by CYP11B2, in the NCI-H295R human adrenocortical cell line as well as ex vivo in mouse and human adrenal tissue. ZG-specific deletion of the regulatory Cn subunit CnB1 diminished Cyp11b2 expression in vivo and disrupted K+-mediated aldosterone synthesis. Phosphoproteomics analysis identified nuclear factor of activated T cells, cytoplasmic 4 (NFATC4), as a target for Cn-mediated dephosphorylation. Deletion of NFATC4 impaired K+-dependent stimulation of CYP11B2 expression and aldosterone production while expression of a constitutively active form of NFATC4 increased expression of CYP11B2 in NCI-H295R cells. Chromatin immunoprecipitation revealed NFATC4 directly regulated CYP11B2 expression. Thus, Cn controls aldosterone production via the Cn/NFATC4 pathway. Inhibition of Cn/NFATC4 signaling may explain low plasma aldosterone levels and hyperkalemia in patients treated with tacrolimus, and the Cn/NFATC4 pathway may provide novel molecular targets to treat primary aldosteronism.
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Affiliation(s)
- Mesut Berber
- Institute of Anatomy, University of Zurich, Switzerland
- Swiss National Centre for Competence in Research “Kidney Control of Homeostasis” (NCCR Kidney.CH), Zurich, Switzerland
| | - Sining Leng
- Department of Pediatrics, Harvard Medical School, Boston Children’s Hospital, Boston, Massachusetts, USA
- Division of Endocrinology, Boston Children’s Hospital, Boston, Massachusetts, USA
| | | | - Denise V. Winter
- Swiss Centre for Applied Human Toxicology and Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland
| | - Alex Odermatt
- Swiss Centre for Applied Human Toxicology and Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland
| | - Felix Beuschlein
- Swiss National Centre for Competence in Research “Kidney Control of Homeostasis” (NCCR Kidney.CH), Zurich, Switzerland
- Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich and University of Zurich, Zurich, Switzerland
- Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Munich, Germany
| | - Johannes Loffing
- Institute of Anatomy, University of Zurich, Switzerland
- Swiss National Centre for Competence in Research “Kidney Control of Homeostasis” (NCCR Kidney.CH), Zurich, Switzerland
| | - David T. Breault
- Department of Pediatrics, Harvard Medical School, Boston Children’s Hospital, Boston, Massachusetts, USA
- Harvard Stem Cell Institute, Cambridge, Massachusetts, USA
| | - David Penton
- Institute of Anatomy, University of Zurich, Switzerland
- Swiss National Centre for Competence in Research “Kidney Control of Homeostasis” (NCCR Kidney.CH), Zurich, Switzerland
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26
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Kate A, Shanbhag SS, Donthineni PR, Amescua G, Quinones VLP, Basu S. Role of topical and systemic immunosuppression in aqueous-deficient dry eye disease. Indian J Ophthalmol 2023; 71:1176-1189. [PMID: 37026249 PMCID: PMC10276741 DOI: 10.4103/ijo.ijo_2818_22] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 12/19/2022] [Accepted: 01/27/2023] [Indexed: 04/08/2023] Open
Abstract
Immunosuppression in aqueous-deficient dry eye disease (ADDE) is required not only to improve the symptoms and signs but also to prevent further progression of the disease and its sight-threatening sequelae. This immunomodulation can be achieved through topical and/or systemic medications, and the choice of one drug over the other is determined by the underlying systemic disease. These immunosuppressive agents require a minimum of 6-8 weeks to achieve their beneficial effect, and during this time, the patient is usually placed on topical corticosteroids. Antimetabolites such as methotrexate, azathioprine, and mycophenolate mofetil, along with calcineurin inhibitors, are commonly used as first-line medications. The latter have a pivotal role in immunomodulation since T cells contribute significantly to the pathogenesis of ocular surface inflammation in dry eye disease. Alkylating agents are largely limited to controlling acute exacerbations with pulse doses of cyclophosphamide. Biologic agents, such as rituximab, are particularly useful in patients with refractory disease. Each group of drugs has its own side-effect profiles and requires a stringent monitoring schedule that must be followed to prevent systemic morbidity. A customized combination of topical and systemic medications is usually required to achieve adequate control, and this review aims to help the clinician choose the most appropriate modality and monitoring regimen for a given case of ADDE.
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Affiliation(s)
- Anahita Kate
- Shantilal Shanghvi Cornea Institue, LV Prasad Eye Institute, Vijayawada, Andhra Pradesh, India
| | - Swapna S Shanbhag
- Shantilal Shanghvi Cornea Institue, LV Prasad Eye Institute, Hyderabad, Telengana, India
| | - Pragnya R Donthineni
- Shantilal Shanghvi Cornea Institue, LV Prasad Eye Institute, Hyderabad, Telengana, India
| | - Guillermo Amescua
- Department of Ophthalmology, Duke Eye Center, Duke University School of Medicine, Durham 27705, NC, USA
| | - Victor L Perez Quinones
- Foster Center for Ocular Immunology, Department of Ophthalmology, Duke Eye Center, Duke University School of Medicine, Durham, North Carolina, USA
| | - Sayan Basu
- Shantilal Shanghvi Cornea Institue, LV Prasad Eye Institute, Hyderabad, Telengana, India
- Center for Ocular Regeneration (CORE), L. V. Prasad Eye Institute, Hyderabad, Telangana, India
- Brien Holden Eye Research Centre, L. V. Prasad Eye Institute, Hyderabad, Telangana, India
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27
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Ichimura H, Chino S, Shiba Y. Cardiac Regeneration Using Pluripotent Stem Cells and Controlling Immune Responses. Heart Lung Circ 2023:S1443-9506(23)00108-7. [PMID: 37029069 DOI: 10.1016/j.hlc.2022.12.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 11/02/2022] [Accepted: 12/05/2022] [Indexed: 04/08/2023]
Abstract
Pluripotent stem cell (PSC)-derived cardiomyocytes are a promising source of cells in myocardial regeneration therapy for end-stage heart failure. Because most previous reports have focussed on xenotransplantation models using immunocompromised animals, studies on immune rejection in allogeneic transplantation models are needed for preclinical and clinical applications. Human leukocyte antigen (HLA) plays an important role in allogeneic transplantation, and cell bank projects are currently underway worldwide to stock induced pluripotent stem cells (iPSCs) generated from healthy individuals with homozygous HLA haplotypes. However, it is difficult to stock iPSCs that match the entire population in these cell banks; thus, several groups have produced hypoimmunogenic PSCs by knocking out HLA. These HLA-knockout PSCs were able to avoid rejection by T cells but still suffered rejection by natural killer (NK) cells caused by 'missing self-recognition'. Recent studies have attempted to generate hypoimmunogenic PSCs with gene editing to inhibit NK cell activation. Regenerative medicine using autologous iPSCs can be an ideal transplantation therapy, but, currently, there are major hurdles to its practical application. Hopefully, further research will resolve these issues. This review provides an overview of the current understanding and progress in this field.
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Affiliation(s)
- Hajime Ichimura
- Department of Regenerative Science and Medicine, Shinshu University School of Medicine, Matsumoto, Japan; Department of Surgery, Division of Cardiovascular Surgery, Shinshu University School of Medicine, Matsumoto, Japan
| | - Shuji Chino
- Department of Surgery, Division of Cardiovascular Surgery, Shinshu University School of Medicine, Matsumoto, Japan
| | - Yuji Shiba
- Department of Regenerative Science and Medicine, Shinshu University School of Medicine, Matsumoto, Japan; Institute for Biomedical Sciences, Shinshu University, Matsumoto, Japan.
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28
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Cheung A, Levitsky J. CAQ Corner: Basic concepts of transplant immunology. Liver Transpl 2023; 29:331-339. [PMID: 37160065 PMCID: PMC9935643 DOI: 10.1002/lt.26501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 04/15/2022] [Accepted: 05/04/2022] [Indexed: 01/12/2023]
Affiliation(s)
- Amanda Cheung
- Division of Gastroenterology and Hepatology, Comprehensive Transplant Center , Northwestern University Feinberg School of Medicine , Chicago , Illinois , USA
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29
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Park JI, Song GW, Ryu JH, Choi ST, Choi NG, Jung BH, Chu CW, Kim KK, Jung DH, Ha TY, Moon DB, Yang K, Shin MH, Chung YK, Hwang S, Yoon YI, Lee SG. A Multicenter, Randomized, Open-Label Study to Compare the Efficacy and Safety of Tacrolimus and Corticosteroids in Combination With or Without Mycophenolate Mofetil in Liver Transplantation Recipients Infected With Hepatitis B Virus. Transplant Proc 2023; 55:387-395. [PMID: 36822884 DOI: 10.1016/j.transproceed.2023.01.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Revised: 12/12/2022] [Accepted: 01/05/2023] [Indexed: 02/24/2023]
Abstract
BACKGROUND Mycophenolate mofetil exhibits pharmacologic mechanisms different from calcineurin inhibitors. Therefore, the dose of calcineurin inhibitors can be reduced along with side effects for effective immunosuppression. We aimed to evaluate the efficacy and safety of tacrolimus and corticosteroid in combination with or without mycophenolate mofetil in living donor liver transplantation (LDLT) recipients infected with hepatitis B virus (HBV). METHODS A randomized, open-label, comparative, multicenter, phase IV study was conducted with 119 patients from January 2014 to September 2017. In the full analysis set population, 58 and 59 patients were included in the study group (triple-drug regimen: TacroBell + My-rept + corticosteroid) and the control group (dual-drug regimen: TacroBell + corticosteroid), respectively. In the per protocol set population, 49 and 42 patients were included in the study and control groups, respectively. RESULTS In the full analysis set population, the incidence of biopsy-proven acute cellular rejection (rejection activity index score ≥4) was 3.4% in the study group; however, this finding was not observed in the control group (P = .468). Hepatitis B virus recurrence was observed in one patient in the control group. No cases of biopsy-proven acute cellular rejection and HBV recurrence were observed in the per protocol set population. The incidences of serious adverse events were 25.9% and 18.0% in the study and control groups, respectively; however, the difference between the groups was not statistically significant (P = .376). CONCLUSION Although the study involved a small number of patients, the triple-drug regimen can be considered safe and effective for immunosuppression after living donor liver transplantation in patients infected with HBV.
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Affiliation(s)
- Jeong-Ik Park
- Department of Surgery, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Republic of Korea
| | - Gi-Won Song
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
| | - Je Ho Ryu
- Department of Surgery, Pusan National University Yangsan Hospital, Pusan National University College of Medicine, Gyeongsangnam-do, Republic of Korea
| | - Sang-Tae Choi
- Department of Surgery, Gachon Gil Hospital, Gacheon University College of Medicine, Incheon, Republic of Korea
| | - Nam-Gyu Choi
- Department of Surgery, Chosun University College of Medicine, Gwangju, Republic of Korea
| | - Bo-Hyun Jung
- Department of Surgery, Inje University Haeundae Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea
| | - Chong Woo Chu
- Department of Surgery, Soon Chun Hyang University Seoul Hospital, Seoul, 04401, Republic of Korea
| | - Keon-Kuk Kim
- Department of Surgery, Cheju Halla General Hospital, Jeju-do, Republic of Korea
| | - Dong-Hwan Jung
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Tae-Yong Ha
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Deok-Bog Moon
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Kwangho Yang
- Department of Surgery, Pusan National University Yangsan Hospital, Pusan National University College of Medicine, Gyeongsangnam-do, Republic of Korea
| | - Min-Ho Shin
- Department of Surgery, Chosun University College of Medicine, Gwangju, Republic of Korea
| | - Yong-Kyu Chung
- Department of Surgery, Inje University Haeundae Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea
| | - Shin Hwang
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Young-In Yoon
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Sung-Gyu Lee
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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30
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Wang X, Jiang S, Fei L, Dong F, Xie L, Qiu X, Lei Y, Guo J, Zhong M, Ren X, Yang Y, Zhao L, Zhang G, Wang H, Tang C, Yu L, Liu R, Patzak A, Persson PB, Hultström M, Wei Q, Lai EY, Zheng Z. Tacrolimus Causes Hypertension by Increasing Vascular Contractility via RhoA (Ras Homolog Family Member A)/ROCK (Rho-Associated Protein Kinase) Pathway in Mice. Hypertension 2022; 79:2228-2238. [PMID: 35938417 PMCID: PMC9993086 DOI: 10.1161/hypertensionaha.122.19189] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND To provide tacrolimus is first-line treatment after liver and kidney transplantation. However, hypertension and nephrotoxicity are common tacrolimus side effects that limit its use. Although tacrolimus-related hypertension is well known, the underlying mechanisms are not. Here, we test whether tacrolimus-induced hypertension involves the RhoA (Ras homolog family member A)/ROCK (Rho-associated protein kinase) pathway in male C57Bl/6 mice. METHODS Intra-arterial blood pressure was measured under anesthesia. The reactivity of renal afferent arterioles and mesenteric arteries were assessed in vitro using microperfusion and wire myography, respectively. RESULTS Tacrolimus induced a transient rise in systolic arterial pressure that was blocked by the RhoA/ROCK inhibitor Fasudil (12.0±0.9 versus 3.2±0.7; P<0.001). Moreover, tacrolimus reduced the glomerular filtration rate, which was also prevented by Fasudil (187±20 versus 281±8.5; P<0.001). Interestingly, tacrolimus enhanced the sensitivity of afferent arterioles and mesenteric arteries to Ang II (angiotensin II), likely due to increased intracellular Ca2+ mobilization and sensitization. Fasudil prevented increased Ang II-sensitivity and blocked Ca2+ mobilization and sensitization. Preincubation of mouse aortic vascular smooth muscle cells with tacrolimus activated the RhoA/ROCK/MYPT-1 (myosin phosphatase targeting subunit 1) pathway. Further, tacrolimus increased cytoplasmic reactive oxygen species generation in afferent arterioles (107±5.9 versus 163±6.4; P<0.001) and in cultured mouse aortic vascular smooth muscle cells (100±7.5 versus 160±23.2; P<0.01). Finally, the reactive oxygen species scavenger Tempol inhibited tacrolimus-induced Ang II hypersensitivity in afferent arterioles and mesenteric arteries. CONCLUSIONS The RhoA/ROCK pathway may play an important role in tacrolimus-induced hypertension by enhancing Ang II-specific vasoconstriction, and reactive oxygen species may participate in this process by activating the RhoA/ROCK pathway.
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Affiliation(s)
- Xiaohua Wang
- Department of Nephrology, Center of Kidney and Urology, the Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China (X.W., S.J., L.F., Y.L., M.Z., C.T., E.Y.L., Z.Z.)
| | - Shan Jiang
- Department of Nephrology, Center of Kidney and Urology, the Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China (X.W., S.J., L.F., Y.L., M.Z., C.T., E.Y.L., Z.Z.)
| | - Lingyan Fei
- Department of Nephrology, Center of Kidney and Urology, the Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China (X.W., S.J., L.F., Y.L., M.Z., C.T., E.Y.L., Z.Z.)
| | - Fang Dong
- Department of Physiology, School of Basic Medical Sciences, Zhejiang University School of Medicine, Hangzhou, China (F.D., X.Q., J.G., H.W., E.Y.L.)
| | - Lanyu Xie
- College of Clinical Medicine, Nanchang University, China (L.X.)
| | - Xingyu Qiu
- Department of Physiology, School of Basic Medical Sciences, Zhejiang University School of Medicine, Hangzhou, China (F.D., X.Q., J.G., H.W., E.Y.L.)
| | - Yan Lei
- Department of Nephrology, Center of Kidney and Urology, the Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China (X.W., S.J., L.F., Y.L., M.Z., C.T., E.Y.L., Z.Z.)
| | - Jie Guo
- Department of Physiology, School of Basic Medical Sciences, Zhejiang University School of Medicine, Hangzhou, China (F.D., X.Q., J.G., H.W., E.Y.L.)
| | - Ming Zhong
- Department of Nephrology, Center of Kidney and Urology, the Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China (X.W., S.J., L.F., Y.L., M.Z., C.T., E.Y.L., Z.Z.)
| | - Xiaoqiu Ren
- Department of Radiation Oncology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China (X.R., Q.W.)
| | - Yi Yang
- Department of Nephrology, the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, China (Y.Y.)
| | - Liang Zhao
- The Children's Hospital, National Clinical Research Center for Child Health, Zhejiang University School of Medicine, Hangzhou, China (L.Z., G.Z.)
| | - Gensheng Zhang
- The Children's Hospital, National Clinical Research Center for Child Health, Zhejiang University School of Medicine, Hangzhou, China (L.Z., G.Z.)
| | - Honghong Wang
- Department of Physiology, School of Basic Medical Sciences, Zhejiang University School of Medicine, Hangzhou, China (F.D., X.Q., J.G., H.W., E.Y.L.)
| | - Chun Tang
- Department of Nephrology, Center of Kidney and Urology, the Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China (X.W., S.J., L.F., Y.L., M.Z., C.T., E.Y.L., Z.Z.)
| | - Luyang Yu
- Institute of Genetics and Regenerative Biology, College of Life Sciences, Zhejiang University, Hangzhou, China (L.Y.)
| | - Ruisheng Liu
- Department of Molecular Pharmacology and Physiology, University of South Florida College of Medicine, Tampa (R.L.)
| | - Andreas Patzak
- Institute of Translational Physiology, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany (A.P., P.B.P., E.Y.L.)
| | - Pontus B Persson
- Institute of Translational Physiology, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany (A.P., P.B.P., E.Y.L.)
| | - Michael Hultström
- Integrative Physiology, Department of Medical Cell Biology, Uppsala University, Sweden (M.H.).,Anesthesiology and Intensive Care Medicine, Department of Surgical Sciences, Uppsala University, Sweden (M.H.)
| | - Qichun Wei
- Department of Radiation Oncology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China (X.R., Q.W.)
| | - En Yin Lai
- Department of Nephrology, Center of Kidney and Urology, the Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China (X.W., S.J., L.F., Y.L., M.Z., C.T., E.Y.L., Z.Z.).,Department of Physiology, School of Basic Medical Sciences, Zhejiang University School of Medicine, Hangzhou, China (F.D., X.Q., J.G., H.W., E.Y.L.).,Institute of Translational Physiology, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany (A.P., P.B.P., E.Y.L.)
| | - Zhihua Zheng
- Department of Nephrology, Center of Kidney and Urology, the Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China (X.W., S.J., L.F., Y.L., M.Z., C.T., E.Y.L., Z.Z.)
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31
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Elezaby A, Dexheimer R, Sallam K. Cardiovascular effects of immunosuppression agents. Front Cardiovasc Med 2022; 9:981838. [PMID: 36211586 PMCID: PMC9534182 DOI: 10.3389/fcvm.2022.981838] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 08/30/2022] [Indexed: 11/26/2022] Open
Abstract
Immunosuppressive medications are widely used to treat patients with neoplasms, autoimmune conditions and solid organ transplants. Key drug classes, namely calcineurin inhibitors, mammalian target of rapamycin (mTOR) inhibitors, and purine synthesis inhibitors, have direct effects on the structure and function of the heart and vascular system. In the heart, immunosuppressive agents modulate cardiac hypertrophy, mitochondrial function, and arrhythmia risk, while in vasculature, they influence vessel remodeling, circulating lipids, and blood pressure. The aim of this review is to present the preclinical and clinical literature examining the cardiovascular effects of immunosuppressive agents, with a specific focus on cyclosporine, tacrolimus, sirolimus, everolimus, mycophenolate, and azathioprine.
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Affiliation(s)
- Aly Elezaby
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, United States
- Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, CA, United States
| | - Ryan Dexheimer
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, United States
| | - Karim Sallam
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, United States
- Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, CA, United States
- *Correspondence: Karim Sallam
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32
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Zhang X, Lichvar A, Chan C, Choi D. Evaluating the Incidence and Risk Factors for Acute Cellular Rejection in a Steroid Sparing Liver Transplant Center. Ann Pharmacother 2022; 57:553-559. [PMID: 36004388 DOI: 10.1177/10600280221120059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Corticosteroids has been the mainstay of immunosuppression (IMS) following liver transplant (LT). With the advent of more potent IMS, complete steroid withdrawal has become possible after LT. However, there is limited data regarding the incidence and risk factors for acute cellular rejection (ACR) in LT recipients on steroid sparing regimens. OBJECTIVE To identify the incidence and risk factors of ACR in LT recipients at an urban LT center utilizing a steroid-sparing IMS regimen. METHODS This was a single center retrospective study evaluating incidence of ACR in adults (>18 years) who received a LT between 01/01/2008 and 6/30/2019 at a steroid-sparing liver transplant center. Data between patients who had ACR and patients who did not were compared and risk factors were identified by multivariate logistic linear regression. RESULTS A total of 266 patients were included in this analysis, of which 18.4% experienced ACR within the first year of LT. Median time to first ACR was 134 (interquartile range [IQR]: 34-246) days. Black race (odds ratio [OR]: 4.39, P < 0.001), continued need for prednisone (OR: 2.80, P = 0.015) and cytomegalovirus (CMV) viremia (OR: 6.27, P < 0.001)) were independent risk factors for ACR. Tacrolimus use was associated with less ACR (OR: 0.33, P = 0.013). CONCLUSION AND RELEVANCE Steroid sparing regimens for IMS post-LT were not associated with an increased incidence of ACR when compared to reported ACR rates in literature. Potential risk factors for ACR include Black race, the use of prednisone maintenance IMS therapy, and CMV viremia.
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Affiliation(s)
- Xunjie Zhang
- University of Illinois at Chicago College of Pharmacy, Chicago, IL, USA
| | - Alicia Lichvar
- Center for Transplantation, University of California San Diego Health, San Diego, CA, USA
| | - Christine Chan
- Division of Gastroenterology and Hepatology, University of Illinois at Chicago College of Medicine, Chicago, IL, USA
| | - David Choi
- Department of Pharmacy, Division of Gastroenterology and Hepatology, University of Chicago Medicine, Chicago, IL, USA
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33
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Danford CJ, Gilroy R. Mammalian Target of Rapamycin and Hepatocellular Carcinoma: The Question's Always There, Until We Choose To Answer It. Liver Transpl 2022; 28:931-932. [PMID: 35289072 DOI: 10.1002/lt.26454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 03/03/2022] [Indexed: 01/13/2023]
Affiliation(s)
| | - Richard Gilroy
- Transplantation Services, Intermountain Medical Center, Murray, UT
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34
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Smedman TM, Guren TK, Tveit KM, Thomsen M, Andersen MH, Line PD, Dueland S. Health-Related Quality of Life in Colorectal Cancer Patients Treated With Liver Transplantation Compared to Chemotherapy. Transpl Int 2022; 35:10404. [PMID: 35707633 PMCID: PMC9189292 DOI: 10.3389/ti.2022.10404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Accepted: 05/12/2022] [Indexed: 11/13/2022]
Abstract
Liver transplantation (LT) for patients with non-resectable colorectal liver metastases (CRLM) offers improved survival and has gained increased interest internationally the last years. The aim of this study was to describe the health-related quality of life (HRQoL) in patients with non-resectable CRLM receiving LT and how baseline HRQoL factors affect overall survival (OS). HRQoL data in the SECA (SEcondary CAncer) LT cohort was compared to data obtained from colorectal cancer patients starting first-line chemotherapy for metastatic disease in a clinical trial and data from a Norwegian normal population. HRQoL data from the QLQ-C30 questionnaire used in the SECA LT study and the NORDIC- VII study were reported. The relationship between patient-reported symptom burden at baseline and OS was investigated. In the SECA study longitudinal HRQoL assessment was used to describe the time until definitive deterioration as well as mean values at different time points. Patients in the SECA and NORDIC-VII studies reported similar baseline HRQoL. The median time until definitive deterioration in the transplanted patients was estimated to 36 months. In the SECA study appetite loss and pain at baseline had negative impact on OS (25.3 versus 71.7 months, p = 0.002 and 39.7 versus 71.7 months, p = 0.038, respectively). Despite a relapse in most of the LT patients the Global Health Score (GHS) remained good. Pain, and especially appetite loss at time of transplantation is associated with poor outcome after LT.
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Affiliation(s)
- Tor Magnus Smedman
- Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- *Correspondence: Tor Magnus Smedman,
| | | | | | | | | | - Pål-Dag Line
- Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
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35
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Aiyegbusi O, McGregor E, McManus SK, Stevens KI. Immunosuppression Therapy in Kidney Transplantation. Urol Clin North Am 2022; 49:345-360. [DOI: 10.1016/j.ucl.2021.12.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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36
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Levitsky J, Kandpal M, Guo K, Zhao L, Kurian S, Whisenant T, Abecassis M. Prediction of Liver Transplant Rejection With a Biologically Relevant Gene Expression Signature. Transplantation 2022; 106:1004-1011. [PMID: 34342962 PMCID: PMC9301991 DOI: 10.1097/tp.0000000000003895] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 05/21/2021] [Accepted: 05/31/2021] [Indexed: 11/26/2022]
Abstract
BACKGROUND Noninvasive biomarkers distinguishing early immune activation before acute rejection (AR) could more objectively inform immunosuppression management in liver transplant recipients (LTRs). We previously reported a genomic profile distinguishing LTR with AR versus stable graft function. This current study includes key phenotypes with other causes of graft dysfunction and uses a novel random forest approach to augment the specificity of predicting and diagnosing AR. METHODS Gene expression results in LTRs with AR versus non-AR (combination of other causes of graft dysfunction and normal function) were analyzed from single and multicenter cohorts. A 70:30 approach (61 ARs; 162 non-ARs) was used for training and testing sets. Microarray data were normalized using a LT-specific vector. RESULTS Random forest modeling on the training set generated a 59-probe classifier distinguishing AR versus non-AR (area under the curve 0.83; accuracy 0.78, sensitivity 0.70, specificity 0.81, positive predictive value 0.54, negative predictive value [NPV] 0.89; F-score 0.61). Using a locked threshold, the classifier performed well on the testing set (accuracy 0.72, sensitivity 0.67, specificity 0.73, positive predictive value 0.48, NPV 0.86; F-score 0.56). Probability scores increased in samples preceding AR versus non-AR, when liver function tests were normal, and decreased following AR treatment (P < 0.001). Ingenuity pathway analysis of the genes revealed a high percentage related to immune responses and liver injury. CONCLUSIONS We have developed a blood-based biologically relevant biomarker that can be detected before AR-associated graft injury distinct from LTR never developing AR. Given its high NPV ("rule out AR"), the biomarker has the potential to inform precision-guided immunosuppression minimization in LTRs.
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Affiliation(s)
- Josh Levitsky
- Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, IL
- Division of Gastroenterology and Hepatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Manoj Kandpal
- Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, IL
- Department of Preventive Medicine, Biostatistics Collaboration Center, Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Kexin Guo
- Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, IL
- Department of Preventive Medicine, Biostatistics Collaboration Center, Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Lihui Zhao
- Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, IL
- Department of Preventive Medicine, Biostatistics Collaboration Center, Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Sunil Kurian
- Scripps Clinic Bio-Repository and Bio-Informatics Core, Scripps Green Hospital, La Jolla, CA
| | - Thomas Whisenant
- Center for Computational Biology and Bioinformatics, School of Medicine, University of California San Diego, San Diego, CA
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37
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Zorzetti N, Lauro A, Khouzam S, Marino IR. Immunosuppression, Compliance, and Tolerance After Orthotopic Liver Transplantation: State of the Art. EXP CLIN TRANSPLANT 2022; 20:3-9. [PMID: 35384800 DOI: 10.6002/ect.mesot2021.l13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Orthotopic liver transplantation is the treatment of choice for several otherwise irreversible forms of acute and chronic liver diseases. Early implemented immunosuppressant regimens have had disappointing results with high rejection rates. However, new drugs have reduced the daily immunosuppression requirements, thereby improving graft and patient survival as well as kidney function. Liver rejection is a T-cell-driven immune response and is the active target of immunosuppressive agents. Immunosuppressants can be divided into pharmacological or biological drugs: the gold standard is the calcineurin inhibitors, steroids, mycophenolate mofetil, and mechanistic target of rapamycin inhibitors. Compliance with these agents is essential, although they can increase the risk of infections and neoplastic diseases. In some patients, graft tolerance can be achieved. Graft tolerance is defined as the absence of acute and chronic rejection in a graft, with normal function and histology in an immunosuppression-free, fully immunocompetent host, usually as the final result of a successful attempt at immunosuppression withdrawal. The occurrence of immunosuppressive-related complications has led to new protocols aimed at protecting renal function and preventing de novo cancer and dysmetabolic syndrome. The backbone of immunosuppression remains calcineurin inhibitors in association with other drugs, mainly over the short-term period. To avoid rejection and the side effects on renal dysfunction, de novo cancer, and cardiovascular syndrome, optimal long-term immunosuppressive therapy should be tailored in liver transplant recipients.
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Affiliation(s)
- Noemi Zorzetti
- From the Department of General Surgery, Ospedale A. Costa, Porretta Terme-Bologna, Italy
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38
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Immunosuppressive drugs and associated complications in abdominal organ transplantation. Curr Opin Crit Care 2022; 28:208-215. [PMID: 35142726 DOI: 10.1097/mcc.0000000000000927] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE OF REVIEW Intensive care management of patients who have undergone organ transplantation of liver, small bowel, pancreas, and/or kidney requires a basic knowledge of immunosuppression principles and the management of immunosuppressive medications. This review highlights the core principles of immunosuppression management in abdominal organ transplantation with a focus on complications arising from immunosuppressive drugs, both in the immediate postoperative period and in long-term usage. RECENT FINDINGS The general principles of management of immunosuppression in the abdominal organ transplant population have remained largely unchanged. Improvements in drug monitoring coupled with improvements in knowledge of pathways involved in allograft rejection have further refined immunosuppressive therapy. Infectious and central nervous system complications remain prevalent and are common complications of immunosuppressive drug therapy. SUMMARY For the intensive care professional who cares for abdominal organ transplant recipients, a foundational knowledge of the core principles of immunosuppression management is essential. In addition, an understanding of the common immunosuppressive drug regimens and the complications associated with these regimens is required for optimal management, risk assessment, and outcomes.
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39
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Chaitou AR, Valmiki S, Valmiki M, Zahid M, Aid MA, Fawzy P, Khan S. New-Onset Diabetes Mellitus (NODM) After Liver Transplantation (LT): The Ultimate Non-diabetogenic Immunosuppressive Therapy. Cureus 2022; 14:e23635. [PMID: 35510006 PMCID: PMC9057316 DOI: 10.7759/cureus.23635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 03/29/2022] [Indexed: 11/05/2022] Open
Abstract
New-onset diabetes mellitus (NODM) is a common long-term complication after liver transplantation (LT). It is thought to be drug-induced in most cases, no matter the underlying disease that cause liver failure and indicated transplantation. Standard post-transplantation (PT) immunosuppressive regimens include prolonged use of calcineurin inhibitors (CNIs), namely tacrolimus (TAC), alongside corticosteroids to avoid acute and chronic graft rejection. This combination is well known for its diabetogenicity. Significant differences between the applied regimens stand out concerning the duration and dosages to prevent the metabolic side effects of these drugs in the long run without compromising the graft's survival. Studies were collected after an extensive research of PubMed database for this very specific topic using the following MeSH keywords in multiple combinations: "Liver Transplantation," "Diabetes Mellitus," "NODM," "Tacrolimus," "Cyclosporine A," and "Steroids." In addition, we used the same keywords for regular searches in Google Scholar. Only the relevant English human studies between 2010 and 2020 were collected except for review articles. Duplicates were eliminated using Mendeley software. Twelve relevant studies directly related to the targeted topic were collected and discussed, including five retrospective cohorts, four prospective cohorts, one clinical trial, one prospective pilot, and one case report. Their topics included primarily the factors increasing the risk of new-onset diabetes mellitus after liver transplantation (NODALT), TAC-based immunosuppression and its relative blood levels affecting the possible development of NODALT, the role of cyclosporine in substituting TAC regimen, and the effect of different steroids-avoiding protocols on the prevention of NODALT. The reviewed studies suggested that lowering the serum concentration of tacrolimus (cTAC) throughout the PT period and eliminating the corticosteroids regimen as early as possible, among other measures, can significantly impact the rate of emergence of NODM. This traditional review tackles the most recent studies about NODALT to establish a comprehensive view on this issue and guide clinicians and researchers for the safest immunosuppressive regimen to date, while maintaining a balanced metabolic profile.
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40
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Tsai H, Wu Y, Liu X, Xu Z, Liu L, Wang C, Zhang H, Huang Y, Wang L, Zhang W, Su D, Khan FU, Zhu X, Yang R, Pang Y, Eriksson JE, Zhu H, Wang D, Jia B, Cheng F, Chen H. Engineered Small Extracellular Vesicles as a FGL1/PD-L1 Dual-Targeting Delivery System for Alleviating Immune Rejection. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2102634. [PMID: 34738731 PMCID: PMC8787398 DOI: 10.1002/advs.202102634] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 08/19/2021] [Indexed: 06/13/2023]
Abstract
There is an urgent need for developing new immunosuppressive agents due to the toxicity of long-term use of broad immunosuppressive agents after organ transplantation. Comprehensive sample analysis revealed dysregulation of FGL1/LAG-3 and PD-L1/PD-1 immune checkpoints in allogeneic heart transplantation mice and clinical kidney transplant patients. In order to enhance these two immunosuppressive signal axes, a bioengineering strategy is developed to simultaneously display FGL1/PD-L1 (FP) on the surface of small extracellular vesicles (sEVs). Among various cell sources, FP sEVs derived from mesenchymal stem cells (MSCs) not only enriches FGL1/PD-L1 expression but also maintain the immunomodulatory properties of unmodified MSC sEVs. Next, it is confirmed that FGL1 and PD-L1 on sEVs are specifically bound to their receptors, LAG-3 and PD-1 on target cells. Importantly, FP sEVs significantly inhibite T cell activation and proliferation in vitro and a heart allograft model. Furthermore, FP sEVs encapsulated with low-dose FK506 (FP sEVs@FK506) exert stronger effects on inhibiting T cell proliferation, reducing CD8+ T cell density and cytokine production in the spleens and heart grafts, inducing regulatory T cells in lymph nodes, and extending graft survival. Taken together, dual-targeting sEVs have the potential to boost the immune inhibitory signalings in synergy and slow down transplant rejection.
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Affiliation(s)
- Hsiang‐i Tsai
- School of Pharmaceutical Sciences (Shenzhen)Sun Yat‐sen UniversityShenzhen518107P. R. China
- Department of Medical ImagingThe Affiliated Hospital of Jiangsu UniversityZhenjiang212001China
| | - Yingyi Wu
- School of Pharmaceutical Sciences (Shenzhen)Sun Yat‐sen UniversityShenzhen518107P. R. China
| | - Xiaoyan Liu
- School of Pharmaceutical Sciences (Shenzhen)Sun Yat‐sen UniversityShenzhen518107P. R. China
| | - Zhanxue Xu
- School of Pharmaceutical Sciences (Shenzhen)Sun Yat‐sen UniversityShenzhen518107P. R. China
| | - Longshan Liu
- Organ Transplant CenterThe First Affiliated HospitalSun Yat‐Sen University58 Zhongshan 2nd RoadGuangzhouGuangdong510080China
| | - Changxi Wang
- Organ Transplant CenterThe First Affiliated HospitalSun Yat‐Sen University58 Zhongshan 2nd RoadGuangzhouGuangdong510080China
| | - Huanxi Zhang
- Organ Transplant CenterThe First Affiliated HospitalSun Yat‐Sen University58 Zhongshan 2nd RoadGuangzhouGuangdong510080China
| | - Yisheng Huang
- Department of Oral SurgeryStomatological HospitalSouthern Medical UniversityGuangzhouGuangdong510280P. R China
| | - Linglu Wang
- School of Pharmaceutical Sciences (Shenzhen)Sun Yat‐sen UniversityShenzhen518107P. R. China
| | - Weixian Zhang
- School of Pharmaceutical Sciences (Shenzhen)Sun Yat‐sen UniversityShenzhen518107P. R. China
| | - Dandan Su
- School of Pharmaceutical Sciences (Shenzhen)Sun Yat‐sen UniversityShenzhen518107P. R. China
| | | | - Xiaofeng Zhu
- School of Traditional Medicine Materials ResourceGuangdong Pharmaceutical University YunfuGuangdong527322China
| | - Rongya Yang
- Department of DermatologyThe Seventh Medical Center of PLA General HospitalPeking100010China
| | - Yuxin Pang
- School of Traditional Medicine Materials ResourceGuangdong Pharmaceutical University YunfuGuangdong527322China
| | - John E. Eriksson
- Cell BiologyBiosciencesFaculty of Science and EngineeringÅbo Akademi UniversityTurkuFI‐20520Finland
| | - Haitao Zhu
- Department of Medical ImagingThe Affiliated Hospital of Jiangsu UniversityZhenjiang212001China
| | - Dongqing Wang
- Department of Medical ImagingThe Affiliated Hospital of Jiangsu UniversityZhenjiang212001China
| | - Bo Jia
- Department of Oral SurgeryStomatological HospitalSouthern Medical UniversityGuangzhouGuangdong510280P. R China
| | - Fang Cheng
- School of Pharmaceutical Sciences (Shenzhen)Sun Yat‐sen UniversityShenzhen518107P. R. China
| | - Hongbo Chen
- School of Pharmaceutical Sciences (Shenzhen)Sun Yat‐sen UniversityShenzhen518107P. R. China
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41
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Hamdeh S, Micic D, Hanauer S. Review article: drug-induced small bowel injury. Aliment Pharmacol Ther 2021; 54:1370-1388. [PMID: 34668591 DOI: 10.1111/apt.16642] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 07/05/2021] [Accepted: 09/29/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND Drug-induced gastrointestinal injury has been increasingly reported, but its exact incidence is not known. The small and large intestines represent the most affected sites of injury, accounting for 20%-40% of all gastrointestinal side effects. AIM To provide an updated literature review detailing medications linked to the development of small bowel injury. METHODS We conducted a literature search on PubMed from its inception to May 1, 2021. We included English-language original studies, meta-analyses, systematic reviews, review articles and case reports. RESULTS Drug-induced enteropathy can range from asymptomatic histological changes resulting in a subtle, self-limited disease to a chronic inflammatory condition mimicking inflammatory bowel disease, or bowel perforation. Endoscopy can demonstrate erythema, mucosal friability, oedema, erosions, ulcers or strictures in severe cases. Histology may include mucosal erosions and ulcerations, focal active enteritis, villous atrophy, epithelial apoptosis or necrotising enteritis. A well-established association has been found with the use of nonsteroidal anti-inflammatory drugs, immunosuppressants, chemotherapeutic agents, antibiotics, immunotherapies, etanercept and olmesartan. Possible associations have been reported with other biologic agents, medications used for glycemic control, antihypertensives, cholinesterase inhibitors, potassium and iron supplements, with conflicting data regarding contraceptives/hormonal therapy and isotretinoin. CONCLUSION Physicians should be aware of the manifestations of drug-induced enteropathy as early recognition can lead to prompt discontinuation of the offending therapy and, therefore, a reduced risk of future complications.
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Affiliation(s)
- Shadi Hamdeh
- Department of Internal Medicine, Division of Gastroenterology, Hepatology and Motility, University of Kansas, Lawrence, KS, USA
| | - Dejan Micic
- Department of Internal Medicine, Section of Gastroenterology, Hepatology and Nutrition, University of Chicago, Chicago, IL, USA
| | - Stephen Hanauer
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
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Shigematsu T, Tajima S, Fu R, Zhang M, Itoyama Y, Tsuchimoto A, Egashira N, Ieiri I. The mTOR inhibitor everolimus attenuates tacrolimus-induced renal interstitial fibrosis in rats. Life Sci 2021; 288:120150. [PMID: 34793770 DOI: 10.1016/j.lfs.2021.120150] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2021] [Revised: 10/26/2021] [Accepted: 11/09/2021] [Indexed: 12/13/2022]
Abstract
AIMS Tacrolimus-a widely used immunosuppressant to prevent allograft rejection after organ transplantation-is nephrotoxic, increasing the risk of kidney injury accompanied by kidney fibrosis. The mammalian target of rapamycin (mTOR) inhibitor, everolimus, is an immunosuppressant used together with tacrolimus. Although mTOR signaling inhibition has been demonstrated to exhibit antifibrotic effects, the efficacy of everolimus against tacrolimus-induced kidney fibrosis has not been explored. Therefore, we evaluated the protective effects of everolimus against tacrolimus-induced kidney fibrosis. MAIN METHODS To assess antifibrotic effect of everolimus against tacrolimus-induced kidney fibrosis, male Wistar rats were subcutaneously administered vehicle or tacrolimus (5 mg/kg per day) and/or everolimus (0.2 mg/kg per day) for 2 weeks after bilateral renal ischemia for 45 min. The antifibrotic effect of everolimus was also assessed using rat kidney fibroblast cell line (NRK-49F). KEY FINDINGS Tacrolimus administration increased predominant profibrotic cytokine transforming growth factor-β (TGF-β) and fibroblast activation marker α-smooth muscle actin (α-SMA) expression and promoted the infiltration of macrophages in the kidney cortex, resulting in renal interstitial fibrosis in rats. Tacrolimus increased serum creatinine, blood urea nitrogen, kidney injury molecule-1 (KIM-1), and kidney injuries, such as tubular dilation, vacuolization, and glomerular atrophy. Everolimus administration attenuated tacrolimus-induced kidney fibrosis and the associated abnormalities. Everolimus strongly suppressed TGF-β-induced kidney fibroblast activation and extracellular matrix protein expression by the mTOR signaling inhibition. SIGNIFICANCE We demonstrated that everolimus attenuates tacrolimus-induced renal interstitial fibrosis in rats. Owing to its protective effect against tacrolimus-induced kidney fibrosis, everolimus may be useful when used concomitantly with tacrolimus.
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Affiliation(s)
- Tomohiro Shigematsu
- Department of Clinical Pharmacology and Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan; Department of Pharmacy, Kyushu University Hospital, Fukuoka, Japan
| | - Soichiro Tajima
- Department of Pharmacy, Kyushu University Hospital, Fukuoka, Japan.
| | - Rao Fu
- Department of Clinical Pharmacology and Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Mengyu Zhang
- Department of Clinical Pharmacology and Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Yuuka Itoyama
- Department of Clinical Pharmacology and Biopharmaceutics, School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Akihiro Tsuchimoto
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Nobuaki Egashira
- Department of Clinical Pharmacology and Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan; Department of Pharmacy, Kyushu University Hospital, Fukuoka, Japan
| | - Ichiro Ieiri
- Department of Clinical Pharmacology and Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan; Department of Pharmacy, Kyushu University Hospital, Fukuoka, Japan
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43
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Ullmann JM, Erbersdobler A. Gastric lanthanosis (lanthanum deposition) in an immunosuppressed patient that discontinued lanthanum carbonate seven years ago. Clin Case Rep 2021; 9:e05075. [PMID: 34815874 PMCID: PMC8594568 DOI: 10.1002/ccr3.5075] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 10/15/2021] [Accepted: 10/26/2021] [Indexed: 11/14/2022] Open
Abstract
A 72-year-old female patient used the oral phosphate binder lanthanum carbonate for 6 years, before discontinuing it after receiving a pancreas and kidney transplant. Now, 7 years after discontinuation, the patient developed bilious emesis. An upper gastrointestinal endoscopy showed an unspecific gastritis. Biopsies showed subepithelial crystalline deposits consistent with gastric lanthanosis.
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Affiliation(s)
- Joana M. Ullmann
- Institute of PathologyUniversity Medicine RostockStrempelstr. 14Rostock18057Germany
| | - Andreas Erbersdobler
- Institute of PathologyUniversity Medicine RostockStrempelstr. 14Rostock18057Germany
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44
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Kim JM, Park PJ, Hong G, Joo DJ, Kim KW, Ryu JH, Han YS, Cho JY, Song GW, Kim BW, Kim DS, Kim SH, Choi ST, You YK, Suh KS, Na YW, Kang KJ, Joh JW. Efficacy and safety of a switch from twice-daily tacrolimus to once-daily generic tacrolimus in stable liver transplant patients. KOREAN JOURNAL OF TRANSPLANTATION 2021; 35:168-176. [PMID: 35769244 PMCID: PMC9235448 DOI: 10.4285/kjt.21.0012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 08/27/2021] [Accepted: 09/09/2021] [Indexed: 11/04/2022] Open
Affiliation(s)
- Jong Man Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Pyoung-Jae Park
- Department of Surgery, Korea University College of Medicine, Seoul, Korea
- Department of Surgery, Korea University Guro Hospital, Seoul, Korea
| | - Geun Hong
- Department of Surgery, Ewha Woman's University School of Medicine, Seoul, Korea
| | - Dong Jin Joo
- Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
| | - Kwan Woo Kim
- Department of Surgery, Dong-A University Hospital, Dong-A University College of Medicine, Busan, Korea
| | - Je Ho Ryu
- Department of Surgery, Pusan National University College of Medicine, Busan, Korea
| | - Young Seok Han
- Department of Surgery, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Jai Young Cho
- Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Gi-Won Song
- Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Bong-Wan Kim
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Ajou University School of Medicine, Suwon, Korea
| | - Dong-Sik Kim
- Department of Surgery, Korea University College of Medicine, Seoul, Korea
| | - Seong Hoon Kim
- Center for Liver Cancer, National Cancer Center, Goyang, Korea
| | - Sang Tae Choi
- Department of Surgery, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon, Korea
| | - Young Kyoung You
- Department of Surgery, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Kyung-Suk Suh
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Yang-Won Na
- Department of Surgery, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Koo Jeong Kang
- Department of Surgery, Keimyung University Dongsan Hospital, Keimyung University School of Medicine, Daegu, Korea
| | - Jae-Won Joh
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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45
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Long-term Follow-up of a Randomized Trial of Tacrolimus or Cyclosporine A Microemulsion in Children Post Liver Transplantation. Transplant Direct 2021; 7:e765. [PMID: 34557582 PMCID: PMC8454910 DOI: 10.1097/txd.0000000000001221] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2019] [Revised: 06/22/2021] [Accepted: 07/04/2021] [Indexed: 11/26/2022] Open
Abstract
The aim of this study was to determine the long-term efficacy and safety of tacrolimus (Tac) and cyclosporine immunosuppression in pediatric liver transplantation (LTx).
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46
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Hamdeh S, Micic D, Hanauer S. Drug-Induced Colitis. Clin Gastroenterol Hepatol 2021; 19:1759-1779. [PMID: 32360808 DOI: 10.1016/j.cgh.2020.04.069] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Revised: 03/31/2020] [Accepted: 04/20/2020] [Indexed: 02/07/2023]
Abstract
Drug-induced colitis encompasses a wide spectrum of colon disorders that can manifest microscopically or macroscopically. Patients present with new-onset colitis or exacerbations of inflammatory bowel diseases; in some cases, colitis resolves with discontinuation of medication. Mucosal injury can be focal or extensive, involving the entire colonic mucosa, and sometimes involves other parts of the gastrointestinal tract. It has been a challenge to determine the proportion of new-onset colitis caused by medication and there are few data on the overall prevalence. We review the drugs that have been linked with development of drug-induced colitis and strategies for physicians who believe their patients have this disorder-usually discontinuation of the drug believed to cause colitis and treatment with steroids or immune-modulating therapies. Physicians must be aware of medications that can cause colitis.
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Affiliation(s)
- Shadi Hamdeh
- Department of Internal Medicine, Division of Gastroenterology, Hepatology and Motility, University of Kansas, Kansas City, Kansas.
| | - Dejan Micic
- Department of Internal Medicine, Section of Gastroenterology, Hepatology and Nutrition, University of Chicago, Chicago, Illinois
| | - Stephen Hanauer
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, Chicago, Illinois
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47
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Lang SA, Bednarsch J, Czigany Z, Joechle K, Kroh A, Amygdalos I, Strnad P, Bruns T, Heise D, Ulmer F, Neumann UP. Liver transplantation in malignant disease. World J Clin Oncol 2021; 12:623-645. [PMID: 34513597 PMCID: PMC8394155 DOI: 10.5306/wjco.v12.i8.623] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 06/15/2021] [Accepted: 07/23/2021] [Indexed: 02/06/2023] Open
Abstract
Liver transplantation for malignant disease has gained increasing attention as part of transplant oncology. Following the implementation of the Milan criteria, hepatocellular carcinoma (HCC) was the first generally accepted indication for transplantation in patients with cancer. Subsequently, more liberal criteria for HCC have been developed, and research on this topic is still ongoing. The evident success of liver transplantation for HCC has led to the attempt to extend its indication to other malignancies. Regarding perihilar cholangiocarcinoma, more and more evidence supports the use of liver transplantation, especially after neoadjuvant therapy. In addition, some data also show a benefit for selected patients with very early stage intrahepatic cholangiocarcinoma. Hepatic epithelioid hemangioendothelioma is a very rare but nonetheless established indication for liver transplantation in primary liver cancer. In contrast, patients with hepatic angiosarcoma are currently not considered to be optimal candidates. In secondary liver tumors, neuroendocrine cancer liver metastases are an accepted but comparability rare indication for liver transplantation. Recently, some evidence has been published supporting the use of liver transplantation even for colorectal liver metastases. This review summarizes the current evidence for liver transplantation for primary and secondary liver cancer.
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Affiliation(s)
- Sven Arke Lang
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Jan Bednarsch
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Zoltan Czigany
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Katharina Joechle
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Andreas Kroh
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Iakovos Amygdalos
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Pavel Strnad
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Tony Bruns
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Daniel Heise
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Florian Ulmer
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Ulf Peter Neumann
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
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48
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Alvarado M, Schaubel DE, Reddy KR, Bittermann T. Black Race Is Associated With Higher Rates of Early-Onset End-Stage Renal Disease and Increased Mortality Following Liver Transplantation. Liver Transpl 2021; 27:1154-1164. [PMID: 33733570 PMCID: PMC8355050 DOI: 10.1002/lt.26054] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Revised: 03/01/2021] [Accepted: 03/08/2021] [Indexed: 12/13/2022]
Abstract
Black race is a risk factor for end-stage renal disease (ESRD). Racial disparities in the risks of early and long-term renal complications after liver transplantation (LT) have not been systematically studied. This study evaluated racial differences in the natural history of acute and chronic renal insufficiency after LT. This was a retrospective single-center cohort study of 763 non-Hispanic White and 181 Black LT recipients between 2008 and 2017. Black race was investigated as an independent predictor of the following outcomes: (1) receipt and duration of early post-LT hemodialysis and (2) time to post-LT ESRD. The interaction of race and post-LT ESRD on survival was also studied. Black recipients had higher rates of pre-LT hypertension (P < 0.001), but diabetes mellitus and renal function before LT were not different by race (all P > 0.05). Overall, 15.2% of patients required early hemodialysis immediately after LT with no difference by race (covariate-adjusted odds ratio, 0.89; P = 0.71). Early dialysis discontinuation was lower among Black recipients (covariate-adjusted hazard ratio [aHR], 0.47; P = 0.02), whereas their rate of post-LT ESRD was higher (aHR, 1.91; P = 0.005). Post-LT survival after ESRD was markedly worse for Black (aHR, 11.18; P < 0.001) versus White recipients (aHR, 5.83; P < 0.001; interaction P = 0.08). Although Black and White LT recipients had comparable pretransplant renal function, post-LT renal outcomes differed considerably, and the impact of ESRD on post-LT survival was greater for Black recipients. This study highlights the need for an individualized approach to post-LT management to improve outcomes for all patients.
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Affiliation(s)
- Meagan Alvarado
- Department of Internal Medicine, University of Pennsylvania, Philadelphia, PA
| | - Douglas E. Schaubel
- Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, PA
| | - K. Rajender Reddy
- Division of Gastroenterology / Transplant Hepatology, University of Pennsylvania, Philadelphia, PA
| | - Therese Bittermann
- Division of Gastroenterology / Transplant Hepatology, University of Pennsylvania, Philadelphia, PA
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Abstract
Tacrolimus is a common immunosuppressant used in solid organ transplant recipients. Although most patients develop diarrheal symptoms, data regarding patterns of injury in patients taking tacrolimus are limited. We performed this study to characterize tacrolimus-related features of colonic injury. We retrospectively identified colonic samples from 20 patients receiving tacrolimus monotherapy. Records were reviewed for symptoms, endoscopic findings, other medications, and infections. None of the patients had gastrointestinal infections or used other drugs known to cause colonic injury; none had received mycophenolate within 6 months of presentation. Cases were evaluated for the nature and distribution of inflammation and crypt abnormalities, including distortion, destruction, and apoptosis. Eighteen (90%) patients were solid organ transplant recipients. Seventeen (85%) had gastrointestinal symptoms, particularly diarrhea (75%). More than 50% had endoscopic colitis and 15% had ulcers and/or erosions. Most (90%) cases showed regenerative epithelial changes; apoptotic crypt cells were present in 55% and numerous in 10% of cases. Neutrophilic cryptitis was present in 60% of cases; 35% showed crypt destruction. Plasma cell-rich lamina propria inflammation and crypt distortion were observed in 40% and 25% of cases, respectively. There was no correlation between therapy duration and features of chronic injury. We conclude that tacrolimus can cause symptomatic colitis. Histologic abnormalities are often mild, featuring regenerative crypts and scattered apoptotic debris. However, 40% of symptomatic patients have chronic colitis, most likely reflecting drug-induced immune dysregulation. Pathologists should be aware of these associations because colitis often resolves with decreasing drug dosage rather than treatment directed toward inflammatory bowel disease.
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50
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Zakerkish F, Soriano MJ, Novella-Mestre E, Brännström M, Díaz-García C. Differential effects of the immunosuppressive calcineurin inhibitors cyclosporine-A and tacrolimus on ovulation in a murine model. Hum Reprod Open 2021; 2021:hoab012. [PMID: 33997300 PMCID: PMC8111498 DOI: 10.1093/hropen/hoab012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 01/22/2021] [Indexed: 11/12/2022] Open
Abstract
STUDY QUESTION Do therapeutic levels of cyclosporine-A and tacrolimus affect ovulation in a rat gonadotrophin-induced ovulation model? SUMMARY ANSWER Cyclosporine-A, but not tacrolimus, decreases ovulation rate when administered for 5 days before induced ovulation. WHAT IS KNOWN ALREADY The mainstays of immunosuppression in solid organ transplantation, to prevent rejection, are the calcineurin inhibitors cyclosporine-A or tacrolimus. These drugs could potentially affect fertility in transplanted patients. Since ovulation is an inflammation-like process with pivotal roles for several immune cells and modulators, it is possible that the calcineurin inhibitors, with broad effects on the immune system, could interfere with this sensitive, biological process. STUDY DESIGN, SIZE, DURATION Experimental design at university-based animal facilities. A total of 45 immature Sprague–Dawley rats were used. The study was carried out over 3 months. PARTICIPANTS/MATERIALS, SETTING, METHODS Immature Sprague–Dawley rats (n = 45) were randomly assigned to receive equivalent doses of tacrolimus (0.5 mg/kg/day; TAC), cyclosporine-A (10 mg/kg/day; CyA) or vehicle (Control). Ovarian hyperstimulation was induced with 10 IU of equine chorionic gonadotrophin, and ovulation was triggered with 10 IU of hCG. Oocytes were retrieved from the oviducts and ovulation rates were calculated. Various subpopulations of white blood cells were counted in peripheral blood and ovarian tissue samples. MAIN RESULTS AND THE ROLE OF CHANCE Animals in the CyA group showed a lower ovulation rate when compared to the TAC and Control groups (CyA: mean 9 oocytes (range 0–22); TAC: 21 oocytes (8–41); Control: 22 oocytes (6–39); P = 0.03). Regarding counts of the white blood cell subpopulations and resident neutrophils in the ovary, no significant differences were observed between the groups. LIMITATIONS, REASONS FOR CAUTION Although the ovulation process is highly conserved within species, the differences between rodents and humans may limit the external translatability of the study. WIDER IMPLICATIONS OF THE FINDINGS These findings suggest that tacrolimus should be the preferred calcineurin inhibitor of choice in transplanted patients who are aiming for pregnancy. STUDY FUNDING/COMPETING INTEREST(S) Swedish Research Council and ALF of Sahlgrenska Academy, Sweden. Rio Hortega Grant from the Instituto de Salud Carlos III, Spain (CM09/00063). There are no conflicts of interest.
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Affiliation(s)
- F Zakerkish
- Department of Obstetrics and Gynecology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - M J Soriano
- Reproductive Medicine Research Group, IIS La Fe, Valencia, Spain
| | - E Novella-Mestre
- Reproductive Medicine Research Group, IIS La Fe, Valencia, Spain
| | - M Brännström
- Department of Obstetrics and Gynecology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - C Díaz-García
- Reproductive Medicine Research Group, IIS La Fe, Valencia, Spain
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