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Deigin V, Linkova N, Vinogradova J, Vinogradov D, Polyakova V, Medvedev D, Krasichkov A, Volpina O. The First Reciprocal Activities of Chiral Peptide Pharmaceuticals: Thymogen and Thymodepressin, as Examples. Int J Mol Sci 2024; 25:5042. [PMID: 38732260 PMCID: PMC11084461 DOI: 10.3390/ijms25095042] [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: 03/15/2024] [Revised: 05/03/2024] [Accepted: 05/03/2024] [Indexed: 05/13/2024] Open
Abstract
Peptides show high promise in the targeting and intracellular delivery of next-generation biotherapeutics. The main limitation is peptides' susceptibility to proteolysis in biological systems. Numerous strategies have been developed to overcome this challenge by chemically enhancing the resistance to proteolysis. In nature, amino acids, except glycine, are found in L- and D-enantiomers. The change from one form to the other will change the primary structure of polypeptides and proteins and may affect their function and biological activity. Given the inherent chiral nature of biological systems and their high enantiomeric selectivity, there is rising interest in manipulating the chirality of polypeptides to enhance their biomolecular interactions. In this review, we discuss the first examples of up-and-down homeostasis regulation by two enantiomeric drugs: immunostimulant Thymogen (L-Glu-L-Trp) and immunosuppressor Thymodepressin (D-Glu(D-Trp)). This study shows the perspective of exploring chirality to remove the chiral wall between L- and D-biomolecules. The selected clinical result will be discussed.
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Affiliation(s)
- Vladislav Deigin
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya St., 16/10, Moscow 117997, Russia; (V.D.); (O.V.)
| | - Natalia Linkova
- St. Petersburg Research Institute of Phthisiopulmonology, Ligovskii Prospect, 2-4, St. Petersburg 191036, Russia;
- St. Petersburg Institute of Bioregulation and Gerontology, 3 Dynamo Ave., St. Petersburg 197110, Russia
| | - Julia Vinogradova
- The Department of Hospital Therapy No. 2, I.M. Sechenov First Moscow State Medical University, 8 Trubetskaya Str., Building 2, Moscow 119991, Russia; (J.V.); (D.V.)
| | - Dmitrii Vinogradov
- The Department of Hospital Therapy No. 2, I.M. Sechenov First Moscow State Medical University, 8 Trubetskaya Str., Building 2, Moscow 119991, Russia; (J.V.); (D.V.)
| | - Victoria Polyakova
- St. Petersburg Research Institute of Phthisiopulmonology, Ligovskii Prospect, 2-4, St. Petersburg 191036, Russia;
- St. Petersburg Institute of Bioregulation and Gerontology, 3 Dynamo Ave., St. Petersburg 197110, Russia
| | - Dmitrii Medvedev
- St. Petersburg Institute of Bioregulation and Gerontology, 3 Dynamo Ave., St. Petersburg 197110, Russia
- The Department of Social Rehabilitation and Occupational Therapy of the St. Petersburg Medical and Social Institute, Kondratievsky St., 72A, St. Petersburg 195271, Russia
| | - Alexander Krasichkov
- Department of Radio Engineering Systems, Saint Petersburg Electrotechnical University ‘LETI’, St. Petersburg 197376, Russia
| | - Olga Volpina
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya St., 16/10, Moscow 117997, Russia; (V.D.); (O.V.)
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Kakuda N, Amiya E, Hatano M, Ishida J, Tsuji M, Bujo C, Yagi H, Fujita K, Ishii S, Isotani Y, Kurihara T, Numata G, Gyoten T, Shimada S, Ando M, Ono M, Komuro I. Effect of renal function under left ventricular assist device support on the cardiac function and clinical events after heart transplantation. Clin Transplant 2023; 37:e15107. [PMID: 37615650 DOI: 10.1111/ctr.15107] [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: 05/31/2023] [Revised: 07/21/2023] [Accepted: 08/14/2023] [Indexed: 08/25/2023]
Abstract
AIM We investigated the effects of pre-transplantation renal dysfunction under left ventricular assisted device (LVAD) support on post-transplantation cardiac function, and patient prognosis after heart transplantation (HTx). METHOD All patients who were bridged by LVAD and underwent HTx at our hospital between 2007 and 2022 were included in this study. Patients were classified into two groups based on estimated glomerular filtration rate (eGFR) before HTx: renal dysfunction (RD) group (eGFR < 60 mL/min/1.73 m2 ) and non-renal dysfunction (NRD) group. RESULT A total of 132 patients were analyzed, of whom 48 were classified into the RD group and 84 into the NRD group (RD group, 47.9 ± 10.1 years; NRD group, 38.4 ± 11.9 years, p < .0001). Under LVAD support before HTx, the RD group tended to have a history of right ventricular failure (RD group, nine (19%); NRD group, seven (8%); p = .098). After HTx, the echocardiographic parameters did not differ between the two groups in the long term. Furthermore, more concise hemodynamic parameters, exemplified by right heart catheterization, were not significantly different between the two groups. Regarding graft rejection, no significant differences were found in acute cellular rejection and cardiac allograft vasculopathy following HTx. In contrast, patients with RD before HTx had significantly increased mortality in the chronic phase after HTx and initiation of maintenance dialysis, without any overt changes in cardiac function. CONCLUSION Pre-transplantation renal dysfunction under LVAD support significantly affected clinical course after HTx without any overt changes in graft cardiac function.
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Affiliation(s)
- Nobutaka Kakuda
- Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Eisuke Amiya
- Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
- Department of Therapeutic Strategy for Heart Failure, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Masaru Hatano
- Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
- Department of Advanced Medical Center for Heart Failure, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Junichi Ishida
- Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Masaki Tsuji
- Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Chie Bujo
- Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Hiroki Yagi
- Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Kanna Fujita
- Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Satoshi Ishii
- Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Yoshitaka Isotani
- Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Takahiro Kurihara
- Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Genri Numata
- Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Takayuki Gyoten
- Department of Cardiac Surgery, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Shogo Shimada
- Department of Cardiac Surgery, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Masahiko Ando
- Department of Cardiac Surgery, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Minoru Ono
- Department of Cardiac Surgery, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Issei Komuro
- Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
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Gunther M, Jiang S, Banga A, Sher Y. Delayed-Onset Psychosis Secondary to Tacrolimus Neurotoxicity After Lung Transplant: A Case Report and Systematic Review. J Acad Consult Liaison Psychiatry 2023; 64:550-561. [PMID: 37778461 DOI: 10.1016/j.jaclp.2023.09.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 08/28/2023] [Accepted: 09/25/2023] [Indexed: 10/03/2023]
Abstract
BACKGROUND Tacrolimus is the most common immunosuppressant used after transplant, yet it can result in moderate-to-severe neurotoxicity in up to 32% of patients. Signs of neurotoxicity can vary from mild (tremor or headache) to severe (posterior reversible encephalopathy syndrome or psychosis. Prompt recognition and management is needed to lead to symptom resolution. OBJECTIVE The objective of this study is to describe the clinical presentation of tacrolimus-induced psychosis, a type of tacrolimus-inducted neurotoxicity, and distinguish it from other central nervous system disturbances, including delirium. METHODS AND RESULTS We present a case of delayed onset tacrolimus-induced psychosis with focus on unique clinical features and management strategies. We conducted a systematic review of cases of tacrolimus-induced psychosis using the PubMed database and included 15 manuscripts in our review. CONCLUSIONS Tacrolimus-induced psychosis is a unique presentation of tacrolimus-related neurotoxicity and can present without the cardinal symptoms of delirium. The data on isolated psychotic symptoms are limited with current literature focusing on more common presentations of tacrolimus-induced neurotoxicity, such as delirium and tremor. Development of psychosis can occur later in the treatment course and at normal tacrolimus serum levels. It can improve with antipsychotic therapies, but primary management should include cross-titration to an alternate immunosuppressant regimen.
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Affiliation(s)
- Matthew Gunther
- Division of Medical Psychiatry, Department of Psychiatry, Stanford University, School of Medicine, Palo Alto, CA.
| | - Shixie Jiang
- Division of Medical Psychiatry, Department of Psychiatry, Stanford University, School of Medicine, Palo Alto, CA
| | - Amit Banga
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Stanford University, School of Medicine, Palo Alto, CA
| | - Yelizaveta Sher
- Division of Medical Psychiatry, Department of Psychiatry, Stanford University, School of Medicine, Palo Alto, CA
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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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Miura K, Yu R, Entwistle TR, McKenzie SC, Green AC. Long-term changes in body weight and serum cholesterol in heart transplant recipients. Clin Transplant 2022; 36:e14819. [PMID: 36074751 PMCID: PMC10909516 DOI: 10.1111/ctr.14819] [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: 04/14/2022] [Revised: 08/27/2022] [Accepted: 09/05/2022] [Indexed: 12/27/2022]
Abstract
INTRODUCTION Long-term changes in weight and blood lipids beyond 12 months after heart transplantation are largely unknown. We quantified changes in weight, body mass index (BMI), blood cholesterol, and triglycerides in heart transplant recipients (HTRs) during the 36 months after transplantation, and we assessed the influence of statin therapy on these outcomes. METHODS Retrospective cohort study of adult HTRs, transplanted 1990-2017, in Queensland, Australia. From each patient's medical charts, we extracted weight, total cholesterol, triglycerides, and statin therapy at four time-points: time of transplant (baseline), and 12-, 24-, 36-month post-transplant. Changes in weight and blood lipids were assessed according to baseline BMI. RESULTS Among 316 HTRs, 236 (median age 52 years, 83% males) with available information were included. During the 36 months post-transplant, all patients gained weight (83.5-90.5 kg; p < .001), especially those with baseline BMI < 25.0 km/m2 (67.9-76.2 kg; p < .001). Mean blood cholesterol (4.60-4.90 mmol/L; p = .004) and mean blood triglycerides (1.79-2.18 mmol/L; p = .006) also increased significantly in all patients, particularly in those with baseline BMI ≥ 25.0 km/m2 but the differences were not significant (total cholesterol 4.42-5.13 mmol/L; triglycerides 1.76-2.47 mmol/L). Total cholesterol was highest in patients not taking statins, and levels differed significantly (p = .010) according to statin dosing changes during the 36 months post-transplant. CONCLUSION Patients demonstrate significant rises in weight and blood lipids in the 36 months after heart transplantation.
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Affiliation(s)
- Kyoko Miura
- Population Health DepartmentQIMR Berghofer Medical Research InstituteHerstonQLDAustralia
- Faculty of MedicineThe University of QueenslandSt LuciaQueenslandAustralia
| | - Regina Yu
- Population Health DepartmentQIMR Berghofer Medical Research InstituteHerstonQLDAustralia
| | | | - Scott C McKenzie
- Faculty of MedicineThe University of QueenslandSt LuciaQueenslandAustralia
- Advanced Heart Failure and Cardiac Transplant UnitThe Prince Charles HospitalChermsideQLDAustralia
| | - Adèle C Green
- Population Health DepartmentQIMR Berghofer Medical Research InstituteHerstonQLDAustralia
- CRUK Manchester Institute and University of ManchesterManchester Academic Health Science CentreManchesterUK
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Wan P, Hou Y, Qiu B, Feng M, Yang T, Luo Y, Xia L, Chen X, Zhang J, Xue F, Xia Q. GRWR Correlates with the Metabolism of Tacrolimus after Pediatric Living Donor Liver Transplantation According to Donor CYP3A5 Polymorphism. BIOMED RESEARCH INTERNATIONAL 2022; 2022:7647754. [PMID: 36349313 PMCID: PMC9637468 DOI: 10.1155/2022/7647754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 10/04/2022] [Accepted: 10/07/2022] [Indexed: 09/08/2024]
Abstract
Objectives Tacrolimus is characterized by high pharmacokinetic variability in combination with a narrow therapeutic range. However, influence of donor CYP3A5 genotype and graft-to-recipient body weight ratio (GRWR) on tacrolimus' pharmacokinetics after pediatric living donor liver transplantation (LDLT) remains unclear. Methods A total of 174 LDLT recipients (<6 y) were grouped according to donor CYP3A5 genotypes (nonexpressor (NEX) or expressor (EX)) and GRWR (<3.0% (SS, small-size) or ≥3.0% (LS, large-size)): SS/NEX (n = 40), SS/EX (n = 38), LS/NEX (n = 48), and LS/EX (n = 48). Pharmacokinetics of tacrolimus and clinical outcomes were analyzed. Results The relationships between the concentration-dose ratio and donor CYP3A5 genotypes and graft size were examined 3, 7, 14, and 30 days after the transplantation. Tacrolimus C0 levels varied greatly among groups, although recipients started with the same initial dosage. LS/EX recipients had significantly lower C0 levels in comparison with those of other groups. The use of CYP3A5-EX-grafts and a greater GRWR both resulted in significantly higher TAC dose requirements and lower C/D ratios. However, the significance of GRWR no longer exists 3 months after transplantation. The multivariate generalized linear mixed model analysis showed that donor CYP3A5 genotypes (F = 11.876; P = 0.01) and GRWR (F = 4.631; P = 0.033) were independent impact factors for C/D ratios 3, 7, 14, and 30 days after transplantation. Donor CYP3A5-EX genotype was associated with significantly increasing risks of infectious complications and significantly lower Cylex ATP values. However, no significant difference was observed in acute rejections among 4 groups. Conclusions Monitoring of C0 levels alone is not reliable to guide tacrolimus administration. Donor CYP3A5 and GRWR both significantly affect tacrolimus pharmacokinetics after pediatric LDLT. The use of Cylex ATP tests would be helpful to avoid overimmunosuppression.
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Affiliation(s)
- Ping Wan
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yuchen Hou
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Bijun Qiu
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Mingxuan Feng
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Taihua Yang
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yi Luo
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Lei Xia
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaosong Chen
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jianjun Zhang
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Feng Xue
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Turkkan S, Basaran FC, Sahin MF, Beyoglu MA, Yilmaz E, Ozay HY, Bindal M, Yazicioglu A, Yekeler E. Everolimus Use in Lung Transplant Recipients. Transplant Proc 2022; 54:2317-2324. [PMID: 36192210 DOI: 10.1016/j.transproceed.2022.08.027] [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: 03/15/2022] [Revised: 08/09/2022] [Accepted: 08/26/2022] [Indexed: 12/01/2022]
Abstract
BACKGROUND Most lung transplantation centers prefer triple immunosuppressive therapy with tacrolimus, mycophenolate mofetil, and corticosteroids. However, to prevent complications and comorbidities caused by tacrolimus, replacing the drug with everolimus has been considered. METHODS This is a retrospective observational study investigating everolimus switch for different reasons. The population was divided into 3 groups: chronic lung allograft dysfunction (CLAD), kidney impairment, and malignant neoplasm groups. We investigated whether we achieved the goal of the switch and the frequency of rejection, cytomegalovirus and fungal infections, and everolimus adverse effects. RESULTS Nineteen patients received everolimus therapy, and 5 of these were for CLAD, 7 for tacrolimus nephrotoxicity, and 7 for explant/de novo malignant neoplasm. The patients were followed up for a mean (SD) of 30 (16.7) months under the therapy. The number of acute cellular rejection, cytomegalovirus infection, and aspergillosis infection cases before switch were 7, 13, and 2, respectively, and 7, 2, and 3 after that. The mean values of creatinine and estimated glomerular filtration rate of the whole population after the switch improved with no statistical significance, whereas it was significant in tacrolimus nephrotoxicity group. Three patients in the CLAD group remained stable after switching, whereas 2 progressed. Only 1 of the 7 patients with malignant neoplasms had a recurrence during 31.1 (16.5) months of median follow-up. Eleven cases of everolimus adverse effects occurred in 9 patients (47.3%), with 2 (10.5%) withdrawal events. Kidney impairment (P = .02) and age (P = .05) stood out as significant risk factors for drug adverse effects. CONCLUSIONS After lung transplant, everolimus can be a safe alternative for immunosuppression with acceptable adverse effects.
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Affiliation(s)
- Sinan Turkkan
- Department of Thoracic Surgery and Lung Transplantation, University of Health Sciences, Ankara City Hospital, Ankara, Turkey.
| | - Fatmanur Celik Basaran
- Department of Thoracic Surgery and Lung Transplantation, University of Health Sciences, Ankara City Hospital, Ankara, Turkey
| | - Mehmet Furkan Sahin
- Department of Thoracic Surgery and Lung Transplantation, University of Health Sciences, Ankara City Hospital, Ankara, Turkey
| | - Muhammet Ali Beyoglu
- Department of Thoracic Surgery and Lung Transplantation, University of Health Sciences, Ankara City Hospital, Ankara, Turkey
| | - Emre Yilmaz
- Department of Thoracic Surgery and Lung Transplantation, University of Health Sciences, Ankara City Hospital, Ankara, Turkey
| | - Hülya Yigit Ozay
- Department of Anesthesiology and Reanimation, University of Health Sciences, Ankara City Hospital, Ankara, Turkey
| | - Mustafa Bindal
- Department of Anesthesiology and Reanimation, University of Health Sciences, Ankara City Hospital, Ankara, Turkey
| | - Alkin Yazicioglu
- Department of Thoracic Surgery and Lung Transplantation, University of Health Sciences, Ankara City Hospital, Ankara, Turkey
| | - Erdal Yekeler
- Department of Thoracic Surgery and Lung Transplantation, University of Health Sciences, Ankara City Hospital, Ankara, Turkey
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Zhang Q, Tian X, Chen G, Yu Z, Zhang X, Lu J, Zhang J, Wang P, Hao X, Huang Y, Wang Z, Gao F, Yang J. A Prediction Model for Tacrolimus Daily Dose in Kidney Transplant Recipients With Machine Learning and Deep Learning Techniques. Front Med (Lausanne) 2022; 9:813117. [PMID: 35712101 PMCID: PMC9197124 DOI: 10.3389/fmed.2022.813117] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 04/22/2022] [Indexed: 11/13/2022] Open
Abstract
Tacrolimus is a major immunosuppressor against post-transplant rejection in kidney transplant recipients. However, the narrow therapeutic index of tacrolimus and considerable variability among individuals are challenges for therapeutic outcomes. The aim of this study was to compare different machine learning and deep learning algorithms and establish individualized dose prediction models by using the best performing algorithm. Therefore, among the 10 commonly used algorithms we compared, the TabNet algorithm outperformed other algorithms with the highest R2 (0.824), the lowest prediction error [mean absolute error (MAE) 0.468, mean square error (MSE) 0.558, and root mean square error (RMSE) 0.745], and good performance of overestimated (5.29%) or underestimated dose percentage (8.52%). In the final prediction model, the last tacrolimus daily dose, the last tacrolimus therapeutic drug monitoring value, time after transplantation, hematocrit, serum creatinine, aspartate aminotransferase, weight, CYP3A5, body mass index, and uric acid were the most influential variables on tacrolimus daily dose. Our study provides a reference for the application of deep learning technique in tacrolimus dose estimation, and the TabNet model with desirable predictive performance is expected to be expanded and applied in future clinical practice.
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Affiliation(s)
- Qiwen Zhang
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Xueke Tian
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Guang Chen
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Ze Yu
- Beijing Medicinovo Technology Co. Ltd, Beijing, China
| | - Xiaojian Zhang
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Jingli Lu
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Jinyuan Zhang
- Beijing Medicinovo Technology Co. Ltd, Beijing, China
| | - Peile Wang
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Xin Hao
- Dalian Medicinovo Technology Co. Ltd, Dalian, China
| | - Yining Huang
- McCormick School of Engineering, Northwestern University, Evanston, IL, United States
| | - Zeyuan Wang
- Beijing Medicinovo Technology Co. Ltd, Beijing, China
| | - Fei Gao
- Beijing Medicinovo Technology Co. Ltd, Beijing, China
| | - Jing Yang
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China
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Konda P, Golamari R, Eisen HJ. Novel Immunosuppression in Solid Organ Transplantation. Handb Exp Pharmacol 2022; 272:267-285. [PMID: 35318509 DOI: 10.1007/164_2021_569] [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] [Indexed: 06/14/2023]
Abstract
Solid organ transplantation and survival has improved tremendously in the last few decades, much of the success has been attributed to the advancements in immunosuppression. While steroids are being replaced and much of the immunosuppressive strategies focus on steroid free regimens, novel agents have introduced in the induction, maintenance, and treatment of acute rejection phase. MTOR inhibitors have helped with the renal sparing side effect from the calcineurin inhibitors, newer agents such as rituximab have decreased the incidence of donor-specific antibodies which led to decreased incidence of acute rejection reactions. In this chapter we discuss the newer therapies directed specifically for solid organ transplantation.
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Affiliation(s)
- Prasad Konda
- Heart and Vascular Institute, Pennsylvania State University/Milton S. Hershey Medical Center, Hershey, PA, USA
| | - Reshma Golamari
- Department of Hospital Medicine, Pennsylvania State University/Milton S. Hershey Medical Center, Hershey, PA, USA
| | - Howard J Eisen
- Heart and Vascular Institute, Pennsylvania State University/Milton S. Hershey Medical Center, Hershey, PA, USA.
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Adie SK, Bitar A, Konerman MC, Dorsch MP, Andrews CA, Pogue K, Park JM. Tacrolimus time in therapeutic range and long-term outcomes in heart transplant recipients. Pharmacotherapy 2021; 42:106-111. [PMID: 34882822 DOI: 10.1002/phar.2653] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 11/17/2021] [Accepted: 11/18/2021] [Indexed: 11/10/2022]
Abstract
STUDY OBJECTIVE Little is known about the association between tacrolimus time in therapeutic range (TTR) within the guideline-recommended targets and heart transplant (HT) patient outcomes. This study evaluated the association of early tacrolimus TTR with rejection and other clinical outcomes during an extended follow-up after HT. DESIGN This was a single-center retrospective cohort study. SETTING The study was conducted at Michigan Medicine (1/1/2006-12/31/2017). PATIENTS HT recipients ≥18 years of age were included. MEASUREMENT The primary end point was the effect of tacrolimus TTR on time to rejection over the entire follow-up period. MAIN RESULTS A total of 137 patients were included with a median follow-up of 53 months. Based on the median TTR of 58%, the patients were divided into the low tacrolimus TTR (n = 68) and high tacrolimus TTR (n = 69) cohort. The high tacrolimus TTR was associated with a significantly lower risk of rejection compared to the low tacrolimus TTR cohort (hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.41-0.98; p = 0.04). A post hoc analysis revealed associations between rejection and TTR when high and low TTR groups were created at different levels. TTR <30% was associated with a 7-fold higher risk of rejection (HR 7.56; 95% CI 1.76-37.6; p < 0.01) and TTR >75% was associated with a 77% lower risk of rejection (HR 0.23; 95% CI 0.08-0.627; p < 0.01). CONCLUSIONS Patients in the higher tacrolimus TTR cohort had a lower risk of rejection. We observed correlations between higher risk of rejection with TTR <30% and lower risk of rejection with TTR >75%. Future studies should focus on validating the optimal TTR cutoff while also exploring a cutoff to delineate high-risk patients for which early interventions to improve tacrolimus TTR may be beneficial.
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Affiliation(s)
- Sarah K Adie
- Department of Pharmacy Service, University of Michigan, Ann Arbor, Michigan, USA
| | - Abbas Bitar
- Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, Michigan, USA
| | - Matthew C Konerman
- Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, Michigan, USA
| | - Michael P Dorsch
- Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA
| | - Chris A Andrews
- Department of Ophthalmology and Visual Sciences, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Kristen Pogue
- Department of Pharmacy Service, University of Michigan, Ann Arbor, Michigan, USA
| | - Jeong M Park
- Department of Pharmacy Service, University of Michigan, Ann Arbor, Michigan, USA.,Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA
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11
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Kirpalani A, Teoh CW, Ng VL, Dipchand AI, Matsuda-Abedini M. Kidney disease in children with heart or liver transplant. Pediatr Nephrol 2021; 36:3595-3605. [PMID: 33599850 DOI: 10.1007/s00467-021-04949-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 12/09/2020] [Accepted: 01/13/2021] [Indexed: 11/27/2022]
Abstract
Over the past few decades, there has been increasing recognition of kidney disease in children with non-kidney solid organ transplantation. The risk of kidney disease in children undergoing heart or liver transplantation is higher than the general population as the underlying disease and its associated management may directly impair kidney function. Both heart and liver failures contribute to hypoperfusion and kidney ischemia before patients reach the point of transplant. The transplant surgery itself can often be complicated by acute kidney injury (AKI), which may be further exacerbated by a complicated postoperative course. In the short- and long-term post-transplant period, these children are at risk of acute illness, exposed to nephrotoxic medications, and susceptible to rare but severe infections and immunologic insults that may contribute to AKI and chronic kidney disease (CKD). In some, CKD can progress to kidney failure with replacement therapy (KFRT). CKD and KFRT are associated with increased morbidity and mortality in this patient population. Therefore, it is critical to monitor for and recognize the risk factors for kidney injury in this population and mitigate these risks. In this paper, the authors provide an overview of kidney disease pertaining to heart and liver transplantation in children with guidance on monitoring, diagnosis, prevention, and management.
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Affiliation(s)
- Amrit Kirpalani
- Division of Nephrology, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8, Canada.,Department of Paediatrics, University of Toronto, Toronto, ON, Canada
| | - Chia Wei Teoh
- Division of Nephrology, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8, Canada.,Department of Paediatrics, University of Toronto, Toronto, ON, Canada
| | - Vicky Lee Ng
- Department of Paediatrics, University of Toronto, Toronto, ON, Canada.,Division of Gastroenterology, Hepatology, and Nutrition, The Hospital for Sick Children, Toronto, ON, Canada
| | - Anne I Dipchand
- Department of Paediatrics, University of Toronto, Toronto, ON, Canada.,Labatt Family Heart Center, The Hospital for Sick Children, Toronto, ON, Canada
| | - Mina Matsuda-Abedini
- Division of Nephrology, The Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8, Canada. .,Department of Paediatrics, University of Toronto, Toronto, ON, Canada.
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12
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Saab AAER, El-hadidi ES, Hussein MM, Shararah MSAEB, Aly HH. Clinical utility of ABCB1 single nucleotide polymorphism on tacrolimus dose requirements in Egyptian liver transplant patients. EGYPTIAN LIVER JOURNAL 2021. [DOI: 10.1186/s43066-021-00127-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Abstract
Background
Liver transplantation (LT) is the only effective radical cure for all types of end-stage liver diseases. Major advances have been made in the field of liver transplantation due to improvements in surgical techniques and organ conservation as well as optimization of intensive care and immunosuppressive management. We aimed to assess the influence of ABCB1 gene polymorphism of liver transplant recipients on blood level and dose requirements of oral tacrolimus, in an attempt to help in designing an individualized tacrolimus regimen for Egyptian liver transplant recipient. The study included 25 liver transplant recipients and their respective 25 donors. All subjects of this study were subjected to full medical history, clinical evaluation, laboratory investigations, and ABCB1 gene polymorphism evaluation by RT-PCR. Tacrolimus concentration was evaluated for all the recipients during the first 3 months post transplantation.
Results
The present study revealed that the presence of CC genotype was significantly correlated to the effect on tacrolimus C/D ratio and weight-adjusted tacrolimus dose during the first week of the first and 2nd months (Z = −2.108, P <0.05) but not the 3rd month post transplantation (p-value >0.05). Subjects carrying CC genotype required higher doses of tacrolimus to achieve the desired trough levels compared to subjects carrying CT and TT genotypes. The same effect was observed over the whole period of the study but the results were statistically non-significant (p-value>0.05). Recipients who received liver tissue from donors carrying CC genotype also required higher doses of tacrolimus and reached lower levels of blood tacrolimus trough levels.
Conclusion
The present study revealed that ABCB1 CC genotype of both recipients and donors of liver transplantation was significantly associated with increased required tacrolimus dose early after liver transplantation reaching statistically significant level in the first week of the first and second months.
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13
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Bubik RJ, Dierkhising RA, Mara KC, Daly RC, Kushwaha SS, Clavell AL, Bernard SA. Malignancy among adult heart transplant recipients following patient-tailored dosing of anti-thymocyte globulin: a retrospective, nested case-control study of individualized dosing. Transpl Int 2021; 34:2175-2183. [PMID: 34411345 DOI: 10.1111/tri.14012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 07/22/2021] [Accepted: 08/13/2021] [Indexed: 11/29/2022]
Abstract
Post-transplant malignancy is diagnosed in approximately 18% of heart transplant patients and is a leading cause of death post-transplant. One modifiable risk factor is the type and amount of immunosuppression received. Contemporary rabbit anti-thymocyte globulin (rATG) dosing strategy using T-cell-guided dosing, and its effect on malignancy in heart transplant patients is unclear. This was a single-center, retrospective chart review of heart transplant recipients receiving rATG for induction. Patients diagnosed with malignancy post-transplant were matched 1:2 to controls using a nested case-control design. The primary endpoint was to determine the relative risk of rATG exposure with the actual incidence of malignancy post-transplant. The secondary endpoint was the impact of maintenance immunosuppression on malignancy risk. Of the 126 patients included in the study, 25 developed malignancy and were matched to 50 control patients. The median cumulative rATG dose in milligrams (mg) between groups was 365 mg in malignancy cases and 480 mg in controls (OR 0.90, 95% CI 0.75-1.08, P = 0.28). In both the univariate and multivariable analysis, there was no statistically significant difference in malignancy risk found with any maintenance immunosuppressant. The results of this study showed that patient-tailored rATG dosing strategies may not be associated with malignancy development as previously thought.
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Affiliation(s)
| | - Ross A Dierkhising
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
| | - Kristin C Mara
- Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA
| | - Richard C Daly
- Division of Cardiovascular Surgery, Mayo Clinic, Rochester, MN, USA.,Divison of Transplantation Surgery, Mayo Clinic, Rochester, MN, USA
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14
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Bajkovec L, Mrzljak A, Likic R, Alajbeg I. Drug-induced gingival overgrowth in cardiovascular patients. World J Cardiol 2021; 13:68-75. [PMID: 33968305 PMCID: PMC8069521 DOI: 10.4330/wjc.v13.i4.68] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 03/01/2021] [Accepted: 03/29/2021] [Indexed: 02/06/2023] Open
Abstract
Drug-induced gingival overgrowth (DIGO) is a pathological growth of gingival tissue, primarily associated with calcium channel blockers and immunosuppressants. Consequently, it is mainly seen in cardiovascular and transplanted patients. Nifedipine remains the main calcium channel blocker related to the development of this unpleasant side-effect. As for immunosuppressants, cyclosporin is the leading causative agent, whereas other drugs from this drug-group, including tacrolimus, have better safety profiles. Accumulated collagen with inflammatory infiltrates is the histological hallmark of this condition. Several factors are involved in the pathogenesis and can increase the risk, such as male gender, younger age, pre-existing periodontal inflammation, and concomitant use of other DIGO-inducing medications. Patients with DIGO may experience severe discomfort, trouble with speech and mastication, pain, and teeth loss, aside from cosmetic implications. Furthermore, these patients also have an increased risk for cardiovascular diseases. The interdisciplinary approach and cooperation with dental care experts are necessary for patient management. Treatment includes discontinuing the drug and switching to one with a better profile, improving oral hygiene, and surgical removal of enlarged tissue. Recognizing the potential of commonly used medications to cause DIGO and its effect on patients' health is necessary for early detection and adequate management of this complication.
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Affiliation(s)
- Lucija Bajkovec
- Institute of Emergency Medicine of Medimurje County, Institute of Emergency Medicine of Međimurje County, Cakovec 40000, Croatia
| | - Anna Mrzljak
- Department of Gastroenterology and Hepatology, University Hospital Center Zagreb, Zagreb 10000, Croatia
- School of Medicine, University of Zagreb, Zagreb 10000, Croatia.
| | - Robert Likic
- Unit for Clinical Pharmacology and TherapeuticsDepartment of Internal Medicine, University Hospital Centre Zagreb, Zagreb 10000, Croatia
| | - Ivan Alajbeg
- Department of Oral Medicine, University of Zagreb School of Dental Medicine and University Hospital Centre Zagreb, Zagreb 10000, Croatia
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15
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Freitas NCC, Cherchiglia ML, Simão C, Alvares-Teodoro J, Acurcio FDA, Guerra AA. Sixteen Years of Heart Transplant in an Open Cohort in Brazil: Analysis of Graft Survival of Patients using Immunosuppressants. Arq Bras Cardiol 2021; 116:744-753. [PMID: 33886722 PMCID: PMC8121390 DOI: 10.36660/abc.20200117] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 06/23/2020] [Accepted: 08/16/2020] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Heart transplant is the main therapeutic alternative for advanced heart failure patients. Several risk factors affect these patients' survival; however, few studies about the topic are available in Brazil. OBJECTIVES To review the survival rates of heart transplant patients in the Brazilian Public Health System (Sistema Único de Saúde - SUS) between 2000 and 2015. METHODS This is a non-concurrent, open cohort study, involving cardiac transplant patients in Brazil. The cumulative survival probability was estimated by the Kaplan-Meier curve, and the curve comparison was done using the Log-Rank test. The Cox model was used to calculate the Hazard-Ratio (HR). Analyses were conducted at the 95% confidence level. RESULTS The heart transplant survival rate median in Brazil, during the period, was 8.3 years. Each additional year in the recipient's age, the occurrence of infections, and the performance of the surgical procedure in the South Region were associated with a higher risk of graft loss. A higher use ratio of immunosuppressants mycophenolate and azathioprine acted as a protection factor. CONCLUSIONS The analyses conducted provide the first information about the median survival time in heart transplant patients in Brazil. The difference noticed among the geographical regions may be related to the different treatment protocols adopted in the country, especially in the early 2000s. The rate of mycophenolate and azathioprine use as a protection factor suggests that, despite the absence of differences among therapeutic strategies, use of these drugs may favor survival of certain patients. The study provides robust epidemiological data, which are relevant for public health.
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Affiliation(s)
- Natália Cristina Cardoso Freitas
- Universidade Federal de Minas GeraisFaculdade de FarmáciaDepartamento de Farmácia SocialBelo HorizonteMGBrasilUniversidade Federal de Minas Gerais - Faculdade de Farmácia - Departamento de Farmácia Social, Belo Horizonte, MG - Brasil.
| | - Mariangela Leal Cherchiglia
- Universidade Federal de Minas GeraisFaculdade de MedicinaDepartamento de Medicina Preventiva e SocialBelo HorizonteMGBrasilUniversidade Federal de Minas Gerais - Faculdade de Medicina - Departamento de Medicina Preventiva e Social, Belo Horizonte, MG - Brasil.
| | - Charles Simão
- Universidade Federal de Minas GeraisFaculdade de MedicinaDepartamento de CirurgiaBelo HorizonteMGBrasilUniversidade Federal de Minas Gerais - Faculdade de Medicina - Departamento de Cirurgia, Belo Horizonte, MG – Brasil.
| | - Juliana Alvares-Teodoro
- Universidade Federal de Minas GeraisFaculdade de FarmáciaDepartamento de Farmácia SocialBelo HorizonteMGBrasilUniversidade Federal de Minas Gerais - Faculdade de Farmácia - Departamento de Farmácia Social, Belo Horizonte, MG - Brasil.
| | - Francisco de Assis Acurcio
- Universidade Federal de Minas GeraisFaculdade de FarmáciaDepartamento de Farmácia SocialBelo HorizonteMGBrasilUniversidade Federal de Minas Gerais - Faculdade de Farmácia - Departamento de Farmácia Social, Belo Horizonte, MG - Brasil.
| | - Augusto Afonso Guerra
- Universidade Federal de Minas GeraisFaculdade de FarmáciaDepartamento de Farmácia SocialBelo HorizonteMGBrasilUniversidade Federal de Minas Gerais - Faculdade de Farmácia - Departamento de Farmácia Social, Belo Horizonte, MG - Brasil.
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16
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Investigating the Role of BAFF and Its Receptors in Renal Transplant Recipients with Chronic Antibody-Mediated Rejection. J Immunol Res 2021; 2021:6654992. [PMID: 33748289 PMCID: PMC7959970 DOI: 10.1155/2021/6654992] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 01/18/2021] [Accepted: 02/08/2021] [Indexed: 12/17/2022] Open
Abstract
Background Kidney transplantation is the best treatment option for end stage renal disease (ESRD), but graft rejection is still a big obstacle that occurs in spite of immunosuppressive therapy. B cells are considered as the major reason for renal graft rejection because of antibody production. Due to their roles in B cell function, we intended to evaluate the B cell activating factor (BAFF) and its receptors including BAFF receptor (BAFF-R), B cell maturation antigen (BCMA), and transmembrane activator and cyclophilin ligand interactor (TACI) in renal transplant patients. Method The study included 40 kidney allograft patients with cAMR, 40 stable kidney allograft patients, and 8 healthy volunteers with normal kidney function. The percentage and absolute number of CD19+ B cells were analyzed by flow cytometry, the serum level of BAFF was analyzed by ELISA, and mRNA expressions of BAFF and BAFF receptors (BAFF-R, BCMA, and TACI) were measured using quantitative real-time PCR. Results The percentage and the absolute number of B cells decreased significantly in stable and cAMR patients compared to healthy individuals. The serum level and gene expression of BAFF, as well as the mRNA level of BCMA, were increased significantly in both cAMR and stable patients compared to healthy volunteers. There was an overexpression of TACI mRNA in cAMR patients compared to stable patients. Conclusions Both soluble protein and mRNA transcript of BAFF increased in transplant recipients. However, BAFF neither at the serum level nor at the mRNA transcript level cannot be a good biomarker for the prediction of cAMR. In addition, expression of TACI, compared to other receptors of BAFF, confers a potential to be used in distinguishing cAMR and stable kidney transplant patients.
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17
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Sperry BW, Qarajeh R, Omer MA, Brandt H, Safley D, Borkon AM, Everley MP, Fendler TJ, Khumri TM, Lawhorn SL, Magalski A, Nassif ME, Vodnala D, Kao AC, Austin BA. Influence of Donor Transmitted and Rapidly Progressive Coronary Vascular Disease on Long-Term Outcomes After Heart Transplantation: A Contemporary Intravascular Ultrasound Analysis. J Card Fail 2021; 27:464-472. [PMID: 33358960 DOI: 10.1016/j.cardfail.2020.12.012] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 12/14/2020] [Accepted: 12/16/2020] [Indexed: 11/26/2022]
Abstract
BACKGROUND Donor-transmitted atherosclerosis (DTA) and rapidly progressive cardiac allograft vasculopathy (CAV) at 1 year are intravascular ultrasound (IVUS)-derived measures shown to predict adverse cardiovascular outcomes in the setting of early generation immunosuppressive agents. Given the paucity of data on the prognostic value of IVUS-derived measurements in the current era, we sought to explore their association with adverse outcomes after heart transplantation. METHODS AND RESULTS This is a retrospective cohort analysis of patients who underwent heart transplantation at our center between January 2009 and June 2016 with baseline and 1-year IVUS. Five IVUS sections were prospectively analyzed for intimal thickness and lumen area. DTA was defined as maximum intimal thickness of 0.5 mm or greater at baseline, and rapidly progressive CAV as an increase in maximum intimal thickness by 0.5 mm or more at 1 year. Our primary analysis assessed the relationship of IVUS and other clinical data on a composite outcome: coronary intervention, CAV stage 2 or 3 (defined by the International Society for Heart and Lung Transplantation 2010 nomenclature), or cardiovascular death. Among 249 patients (mean age 51.0 ± 12.2 years and 74.3% male) included in the analysis, DTA was detected in 118 patients (51.4%). Over a median follow-up of 6.1 years (interquartile range 4.2-8.0 years), 45 patients met the primary end point (23 percutaneous coronary intervention, 11 CAV 2 or 3, and 11 cardiovascular deaths as first event). DTA and rapidly progressive CAV were not associated with the primary end point, all-cause mortality, or retransplantation. In an additional analysis including post-transplant events, incident rejection was strongly associated with poor outcomes, although cytomegalovirus infection was not. CONCLUSIONS In this contemporary cohort, IVUS-derived DTA and rapidly progressive CAV were not associated with medium- to long-term adverse events after heart transplantation.
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Affiliation(s)
- Brett W Sperry
- Saint Luke's Mid America Heart Institute, Kansas City, Missouri; University of Missouri-Kansas City School of Medicine, Kansas City, Missouri.
| | - Raed Qarajeh
- University of Missouri-Kansas City School of Medicine, Kansas City, Missouri
| | - Mohamed A Omer
- University of Missouri-Kansas City School of Medicine, Kansas City, Missouri
| | - Hunter Brandt
- Saint Luke's Mid America Heart Institute, Kansas City, Missouri; University of Missouri-Kansas City School of Medicine, Kansas City, Missouri
| | - David Safley
- Saint Luke's Mid America Heart Institute, Kansas City, Missouri; University of Missouri-Kansas City School of Medicine, Kansas City, Missouri
| | - A Michael Borkon
- Saint Luke's Mid America Heart Institute, Kansas City, Missouri; University of Missouri-Kansas City School of Medicine, Kansas City, Missouri
| | - Mark P Everley
- Saint Luke's Mid America Heart Institute, Kansas City, Missouri; University of Missouri-Kansas City School of Medicine, Kansas City, Missouri
| | - Timothy J Fendler
- Saint Luke's Mid America Heart Institute, Kansas City, Missouri; University of Missouri-Kansas City School of Medicine, Kansas City, Missouri
| | - Taiyeb M Khumri
- Saint Luke's Mid America Heart Institute, Kansas City, Missouri; University of Missouri-Kansas City School of Medicine, Kansas City, Missouri
| | - Stephanie L Lawhorn
- Saint Luke's Mid America Heart Institute, Kansas City, Missouri; University of Missouri-Kansas City School of Medicine, Kansas City, Missouri
| | - Anthony Magalski
- Saint Luke's Mid America Heart Institute, Kansas City, Missouri; University of Missouri-Kansas City School of Medicine, Kansas City, Missouri
| | - Michael E Nassif
- Saint Luke's Mid America Heart Institute, Kansas City, Missouri; University of Missouri-Kansas City School of Medicine, Kansas City, Missouri
| | - Deepthi Vodnala
- Saint Luke's Mid America Heart Institute, Kansas City, Missouri; University of Missouri-Kansas City School of Medicine, Kansas City, Missouri
| | - Andrew C Kao
- Saint Luke's Mid America Heart Institute, Kansas City, Missouri; University of Missouri-Kansas City School of Medicine, Kansas City, Missouri
| | - Bethany A Austin
- Saint Luke's Mid America Heart Institute, Kansas City, Missouri; University of Missouri-Kansas City School of Medicine, Kansas City, Missouri
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Effectiveness and safety of tacrolimus with or without eltrombopag, as a part of immunosuppressive treatment of aplastic anemia in adults: a retrospective case series. Ann Hematol 2021; 100:933-939. [PMID: 33420879 PMCID: PMC7960622 DOI: 10.1007/s00277-021-04401-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2020] [Accepted: 01/03/2021] [Indexed: 11/03/2022]
Abstract
First-line treatment of aplastic anemia(AA) and for AA patients ineligible for hematopoietic stem cell transplantation (HSCT) has consisted of antithymocyte globulin (ATG), the calcineurin inhibitor cyclosporine A (CsA), and more recently eltrombopag. However, at our institution, we have successfully substituted another calcineurin inhibitor, tacrolimus, as a part of immunosuppressive threatment (IST) for AA due to more favorable toxicity profile. Since there is limited data on the use of tacrolimus in aplastic anemia, we conducted a retrospective review of twenty patients treated with tacrolimus-based immunosuppressive therapy (IST) as a first- or second-line treatment. The overall response rate was comparable to that of patients treated with CsA (18 patients). However, there were no cutaneous side effects observed in patients receiving tacrolimus, a relatively common finding with CsA use. Our data suggest that tacrolimus-based IST is a potential option in AA and might have a more favorable toxicity profile compared to CsA.
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19
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Benazzo A, Cho A, Nechay A, Schwarz S, Frommlet F, Wekerle T, Hoetzenecker K, Jaksch P. Combined low-dose everolimus and low-dose tacrolimus after Alemtuzumab induction therapy: a randomized prospective trial in lung transplantation. Trials 2021; 22:6. [PMID: 33397442 PMCID: PMC7783986 DOI: 10.1186/s13063-020-04843-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Accepted: 10/23/2020] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND Long-term outcomes of lung transplantation are severely affected by comorbidities and development of chronic rejection. Among the comorbidities, kidney insufficiency is one of the most frequent and it is mainly caused by the cumulative effect of calcineurin inhibitors (CNIs). Currently, the most used immunosuppression protocols worldwide include induction therapy and a triple-drug maintenance immunosuppression, with one calcineurin inhibitor, one anti-proliferative drug, and steroids. Our center has pioneered the use of alemtuzumab as induction therapy, showing promising results in terms of short- and long-term outcomes. The use of alemtuzumab followed by a low-dose double drug maintenance immunosuppression, in fact, led to better kidney function along with excellent results in terms of acute rejection, chronic lung allograft dysfunction, and survival (Benazzo et al., PLoS One 14(1):e0210443, 2019). The hypothesis driving the proposed clinical trial is that de novo introduction of low-dose everolimus early after transplantation could further improve kidney function via a further reduction of tacrolimus. Based on evidences from kidney transplantation, moreover, alemtuzumab induction therapy followed by a low-dose everolimus and low-dose tacrolimus may have a permissive action on regulatory immune cells thus stimulating allograft acceptance. METHODS A randomized prospective clinical trial has been set up to answer the research hypothesis. One hundred ten patients will be randomized in two groups. Treatment group will receive the new maintenance immunosuppression protocol based on low-dose tacrolimus and low-dose everolimus and the control group will receive our standard immunosuppression protocol. Both groups will receive alemtuzumab induction therapy. The primary endpoint of the study is to analyze the effect of the new low-dose immunosuppression protocol on kidney function in terms of eGFR change. The study will have a duration of 24 months from the time of randomization. Immunomodulatory status of the patients will be assessed with flow cytometry and gene expression analysis. DISCUSSION For the first time in the field of lung transplantation, this trial proposes the combined use of significantly reduced tacrolimus and everolimus after alemtuzumab induction. The new protocol may have a twofold advantage: (1) further reduction of nephrotoxic tacrolimus and (2) permissive influence on regulatory cells development with further reduction of rejection episodes. TRIAL REGISTRATION EUDRACT Nr 2018-001680-24. Registered on 15 May 2018.
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Affiliation(s)
| | - Ara Cho
- Medizinische Universitat Wien, Vienna, Austria
| | - Anna Nechay
- Medizinische Universitat Wien, Vienna, Austria
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Pilch NA, Bowman LJ, Taber DJ. Immunosuppression trends in solid organ transplantation: The future of individualization, monitoring, and management. Pharmacotherapy 2020; 41:119-131. [PMID: 33131123 DOI: 10.1002/phar.2481] [Citation(s) in RCA: 90] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 08/07/2020] [Accepted: 08/09/2020] [Indexed: 12/20/2022]
Abstract
Immunosuppression regimens used in solid organ transplant have evolved significantly over the past 70 years in the United States. Early immunosuppression and targets for allograft success were measured by incidence and severity of allograft rejection and 1-year patient survival. The limited number of agents, infancy of human leukocyte antigen (HLA) matching techniques and lack of understanding of immunoreactivity limited the early development of effective regimens. The 1980s and 1990s saw incredible advancements in these areas, with acute rejection rates halving in a short span of time. However, the constant struggle to achieve the optimal balance between under- and overimmunosuppression is weaved throughout the history of transplant immunosuppression. The aim of this paper is to discuss the different eras of immunosuppression and highlight the important milestones that were achieved while also discussing this in the context of rational agent selection and regimen design. This discussion sets the stage for how we can achieve optimal long-term outcomes during the next era of immunosuppression, which will move from universal protocols to patient-specific optimization.
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Affiliation(s)
- Nicole A Pilch
- Department of Pharmacy Practice and Outcomes Sciences, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Lyndsey J Bowman
- Department of Pharmacy, Tampa General Hospital, Tampa, Florida, USA
| | - David J Taber
- Department of Surgery, Medical University of South Carolina, Charleston, South Carolina, USA.,Department of Pharmacy Services, Ralph H. Johnson VAMC, Charleston, South Carolina, USA
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Ong PW, Kee T, Ho QY. Impact of tacrolimus versus cyclosporine on one-year renal transplant outcomes: A single-centre retrospective cohort study. PROCEEDINGS OF SINGAPORE HEALTHCARE 2020. [DOI: 10.1177/2010105820957370] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Background:Calcineurin inhibitors are the cornerstone of maintenance immunosuppression after kidney transplant. While studies on predominantly Caucasian populations recommend tacrolimus over cyclosporine, the effects on Singapore’s local population remain unclear.Objectives:This study aimed to compare the impact of tacrolimus against cyclosporine on post-transplant outcomes in our local kidney transplant population.Methods:A single-centre retrospective chart review was conducted on ABO- and human leucocyte antigen (HLA)-compatible kidney transplantations between 1 January 2011 and 15 August 2018. Patients who received basiliximab induction, prednisolone, mycophenolate and either tacrolimus or cyclosporine were included and followed up for at least one year. Recipients of transplantations at other institutions or other immunosuppressive regimens were excluded. Patient and graft outcomes and adverse effects were collected.Results:Overall, 120 patients on tacrolimus and 49 on cyclosporine were included. Patients on tacrolimus were older. This group had more deceased donor transplants, a higher proportion with donor-specific antibodies (DSAs) present and more HLA mismatches. There were no differences in patient and graft survival, graft function and acute rejections at one year, despite adjusting for age, transplant type, presence of DSAs and total HLA mismatches. The tacrolimus group had more infectious admissions (odds ratio=0.27, 95% confidence interval 0.098–0.73, p=0.01) after adjusting for age, transplant type, HLA mismatches, presence of DSAs and acute rejections, with increased severity and more opportunistic infections. More patients on cyclosporine required a change to alternative immunosuppressants (p=0.003).Conclusion:Our study demonstrated comparable short-term post-transplant outcomes between cyclosporine and tacrolimus. Tacrolimus appears more tolerable but may be associated with infection risks.
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Affiliation(s)
- Pei Wen Ong
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore
| | - Terence Kee
- Department of Renal Medicine, Singapore General Hospital, Singapore
| | - Quan Yao Ho
- Department of Renal Medicine, Singapore General Hospital, Singapore
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22
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Racca V, Scaglione A, De Maria R, Panzarino C, Santangelo MA, Cipriani M. Hypomagnesemia after heart transplantation or left ventricular assist device implant for end-stage heart failure. Clin Transplant 2020; 34:e13902. [PMID: 32406532 DOI: 10.1111/ctr.13902] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2020] [Revised: 05/05/2020] [Accepted: 05/06/2020] [Indexed: 12/28/2022]
Abstract
BACKGROUND Patients with advanced heart failure undergoing heart transplant (HTx) or left ventricular assist device (LVAD) implant are at high risk of magnesium deficiency, that may favor development of diabetes. We aimed to comparatively assess prevalence and correlates of hypomagnesemia during cardiac rehabilitation between 51 HTx and 46 LVAD recipients. METHODS AND RESULTS We measured serum magnesium and correlated it to clinical and laboratory findings upon admission (T1 ) and at discharge (T2) from cardiac rehabilitation. Among LVAD, magnesium levels increased from admission to discharge. Among HTx, magnesium concentrations were below normal in 33% and 47% at T1 and T2 , respectively, and decreased from admission to discharge. HTx on tacrolimus showed greater decreases in magnesium and increases in glucose levels than those on cyclosporine. Magnesium levels were inversely associated with >15 mg/dL increased glucose concentrations between T2 and T1 (HR 0.373, 95% CI 0.154-0.903, P = .029) after adjustment for pre-existing diabetes, insulin resistance markers, calcineurin inhibitors (cyclosporine/tacrolimus), prednisone doses, and magnesium supplementation. CONCLUSION Hypomagnesemia is rare in LVAD recipients, but common within 1 month from HTx, worsens during rehabilitation, despite immunosuppression tapering and magnesium supplements, and is independently associated to increasing glucose levels. Studies evaluating whether correcting hypomagnesemia improves outcome are warranted.
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Affiliation(s)
- Vittorio Racca
- Cardiac Rehabilitation, Santa Maria Nascente Institute IRCCS - Fondazione Don Carlo Gnocchi Onlus, Milan, Italy
| | - Anna Scaglione
- Cardiac Rehabilitation, Santa Maria Nascente Institute IRCCS - Fondazione Don Carlo Gnocchi Onlus, Milan, Italy
| | - Renata De Maria
- Cardiac Rehabilitation, Santa Maria Nascente Institute IRCCS - Fondazione Don Carlo Gnocchi Onlus, Milan, Italy
| | - Claudia Panzarino
- Cardiac Rehabilitation, Santa Maria Nascente Institute IRCCS - Fondazione Don Carlo Gnocchi Onlus, Milan, Italy
| | - Maria Antonia Santangelo
- Central Laboratory, Santa Maria Nascente Institute IRCCS - Fondazione Don Carlo Gnocchi Onlus, Milan, Italy
| | - Manlio Cipriani
- Heart Failure and Heart Transplant Program, CardioThoracic and Vascular Department, Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda, Milan, Italy
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23
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Acquaro M, Scelsi L, Pellegrini C, Greco A, Klersy C, Guida S, Raineri C, Ghio S, Turco A, Cattadori B, D'Armini AM, Pelenghi S, Visconti LO. Long-Term Effects of the Replacement of Calcineurin Inhibitors With Everolimus and Mycophenolate in Patients With Calcineurin Inhibitor-Related Nephrotoxicity. Transplant Proc 2020; 52:836-842. [PMID: 32113691 DOI: 10.1016/j.transproceed.2020.01.030] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Accepted: 01/10/2020] [Indexed: 12/25/2022]
Abstract
BACKGROUND There is little evidence on the long-term effects of calcineurin inhibitor (CNI) withdrawal and substitution with everolimus and mycophenolate mofetil in maintenance therapy of patients who have received heart transplants and have concurrent CNI nephrotoxicity. Aims of this study were to evaluate the progression of renal dysfunction after discontinuation of CNIs and to monitor for major adverse events after therapy change. METHODS Data from 41 patients who underwent heart transplant and have different degrees of renal dysfunction (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2), without evidence of proteinuria, and in whom CNI therapy was replaced by everolimus, were analyzed. At the time of CNI withdrawal, clinical parameters, echocardiographic data, blood tests of renal function, and monitoring of adverse events were recorded. The median follow-up period was 5 years ± 28 months. RESULTS In 52% of patients, there was a clear improvement in renal function (10.5 mL/min/1.73 m2 of extra eGFR on average). The former were characterized by less advanced age and a short time from the heart transplant. The echocardiographic parameters showed a significant reduction in septum thickness (11.58 ± 2 mm vs 10.29 ± 2 mm; P = .0001) and in left ventricle posterior wall thickness (10.74 ± 1 mm vs 9.74 ± 1 mm; P = .0004). The incidence of late acute rejection and cardiac allograft vasculopathy was similar in our population compared to literature data. CONCLUSIONS A therapeutic switch from CNIs to everolimus and mycophenolate mofetil can improve renal function in patients with CNI nephrotoxicity, especially in those with a shorter time period from transplantation, without exposing them to a higher incidence of late acute rejection and cardiac allograft vasculopathy.
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Affiliation(s)
- Mauro Acquaro
- Division of Cardiology, Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Laura Scelsi
- Division of Cardiology, Fondazione IRCCS San Matteo Hospital, Pavia, Italy.
| | - Carlo Pellegrini
- Division of Cardiac Surgery, Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Alessandra Greco
- Division of Cardiology, Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Catherine Klersy
- Division of Cardiology, Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Stefania Guida
- Division of Cardiology, Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Claudia Raineri
- Division of Cardiology, Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Stefano Ghio
- Division of Cardiology, Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Annalisa Turco
- Division of Cardiology, Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Barbara Cattadori
- Division of Cardiac Surgery, Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | | | - Stefano Pelenghi
- Division of Cardiac Surgery, Fondazione IRCCS San Matteo Hospital, Pavia, Italy
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Ezquer-Garin C, Ferriols-Lisart R, Alós-Almiñana M. Stability of tacrolimus ophthalmic solution. Am J Health Syst Pharm 2019. [PMID: 28645998 DOI: 10.2146/ajhp160169] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
PURPOSE The stability of 0.3-mg/mL tacrolimus ophthalmic solution at different storage temperatures was studied. METHODS A sterile ophthalmic solution of 0.3 mg/mL tacrolimus was prepared in triplicate under aseptic conditions by diluting tacrolimus in eye drops. Three aliquots of this solution were transferred into polypropylene bottles and stored at 25, 2-8, or -15 to -25 °C. Samples were collected immediately after preparation and at selected time points and assayed in triplicate using high-performance liquid chromatography (HPLC). Samples were also visually examined for macroscopic changes. The 0.3-mg/mL tacrolimus solution was also exposed to acidic treatment and heat to force its degradation and to evaluate the selectivity of the analytic method. The tacrolimus ophthalmic solution was considered stable if at least 90% of the mean initial concentration remained when analyzed by HPLC. RESULTS When stored at 2-8 °C and between -15 and -25 °C, at least 90% of the initial tacrolimus concentration remained throughout the 85-day study period. There were no significant differences in tacrolimus concentrations between the starting and ending points (p > 0.05). However, when tacrolimus solution was stored at 25 °C, the percentage of the initial tacrolimus concentration remaining had decreased to less than 90% on day 28. CONCLUSION Tacrolimus diluted to 0.3 mg/mL in eye drop solution was stable for 20 days when stored at 25 °C and for at least 85 days when stored at 2-8 °C or between -15 and -25 °C in polypropylene bottles and protected from light.
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Affiliation(s)
- Carlos Ezquer-Garin
- INCLIVA Institute for Health Research, University of Valencia, Valencia, Spain .,Hospital Clinico Universitario de Valencia, Valencia, Spain.
| | - Rafael Ferriols-Lisart
- Clinical Pharmacokinetics Laboratory, INCLIVA Institute for Health Research, University of Valencia, Valencia, Spain.,Department of Pharmacy, Hospital Clinico Universitario de Valencia, Valencia, Spain
| | - Manuel Alós-Almiñana
- INCLIVA Institute for Health Research, University of Valencia, Valencia, Spain.,Department of Pharmacy, Hospital Clinico Universitario de Valencia, Valencia, Spain
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25
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Baker WL, Steiger S, Martin S, Patel N, Radojevic J, Darsaklis K, O'Bara L, Kutzler H, Dougherty J, Feingold A, Hammond J, Fusco D, Gluck JA. Association Between Time-in-Therapeutic Tacrolimus Range and Early Rejection After Heart Transplant. Pharmacotherapy 2019; 39:609-613. [PMID: 30892740 DOI: 10.1002/phar.2262] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Historically, there is perceived pressure to achieve therapeutic levels of tacrolimus quickly after heart transplant (HT). We evaluated the association between time within therapeutic tacrolimus range and time to therapeutic trough and rejection in the 30 days following HT. METHODS This is a single-center retrospective cohort study of consecutive adult HT patients receiving immunosuppression. Goal trough tacrolimus levels were 10-15 ng/ml. Surveillance endomyocardial biopsies were performed weekly for 4 weeks. Outcomes included the effect of time to and time-in-therapeutic tacrolimus range (Rosendaal method) on 30-day clinical rejection, 1R/1B, and 2R or higher histologic occurrences. RESULTS We reviewed 67 HT patients (median age 58.8 yrs). For clinical rejection versus no-rejection groups, the median (25th, 75th percentile) time to therapeutic tacrolimus levels was 9.5 (8, 12.3) days versus 9.0 (7, 13) days (p=0.623). The median time-in-therapeutic tacrolimus range was 34.1% (23.2, 42.2) versus 36.2% (19.9, 51.2), respectively (p=0.512). Similarly, we observed no significant differences in time to and time-in-therapeutic tacrolimus range in patients who developed grade 1R/1B (p=0.650 and p=0.725) or grade 2R or higher histology (p=0.632 and p=0.933). CONCLUSIONS Our small single-center analysis suggests that neither time to nor time in therapeutic tacrolimus range predicted acute rejection within 30 days of HT.
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Affiliation(s)
- William L Baker
- Department of Pharmacy Practice, University of Connecticut School of Pharmacy, Storrs, Connecticut.,Department of Pharmacy, Hartford Hospital, Hartford, Connecticut
| | - Samantha Steiger
- Department of Pharmacy, Hartford Hospital, Hartford, Connecticut
| | - Spencer Martin
- Department of Pharmacy, Hartford Hospital, Hartford, Connecticut
| | - Nirav Patel
- Division of Cardiology, Hartford Hospital, Hartford, Connecticut.,Heart and Vascular Institute, Hartford HealthCare, Hartford, Connecticut
| | - Joseph Radojevic
- Division of Cardiology, Hartford Hospital, Hartford, Connecticut.,Heart and Vascular Institute, Hartford HealthCare, Hartford, Connecticut
| | - Konstadina Darsaklis
- Division of Cardiology, Hartford Hospital, Hartford, Connecticut.,Heart and Vascular Institute, Hartford HealthCare, Hartford, Connecticut
| | - Lynn O'Bara
- Division of Cardiology, Hartford Hospital, Hartford, Connecticut
| | - Heather Kutzler
- Department of Pharmacy, Hartford Hospital, Hartford, Connecticut
| | - James Dougherty
- Division of Cardiology, Hartford Hospital, Hartford, Connecticut.,Heart and Vascular Institute, Hartford HealthCare, Hartford, Connecticut
| | - Andrew Feingold
- Division of Cardiology, Hartford Hospital, Hartford, Connecticut.,Heart and Vascular Institute, Hartford HealthCare, Hartford, Connecticut
| | - Jonathan Hammond
- Division of Cardiology, Hartford Hospital, Hartford, Connecticut.,Heart and Vascular Institute, Hartford HealthCare, Hartford, Connecticut
| | - Daniel Fusco
- Division of Cardiology, Hartford Hospital, Hartford, Connecticut.,Heart and Vascular Institute, Hartford HealthCare, Hartford, Connecticut
| | - Jason A Gluck
- Division of Cardiology, Hartford Hospital, Hartford, Connecticut.,Heart and Vascular Institute, Hartford HealthCare, Hartford, Connecticut
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26
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Drug-induced hypertension: Know the problem to know how to deal with it. Vascul Pharmacol 2019; 115:84-88. [DOI: 10.1016/j.vph.2019.02.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2019] [Accepted: 02/17/2019] [Indexed: 01/11/2023]
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27
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Incidence, Risk Factors and Outcomes of Early Acute Kidney Injury After Heart Transplantation: An 18-year Experience. Transplantation 2018; 102:1901-1908. [DOI: 10.1097/tp.0000000000002293] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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28
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Association of Whole Blood Tacrolimus Concentrations with Kidney Injury in Heart Transplantation Patients. Eur J Drug Metab Pharmacokinet 2018; 43:311-320. [PMID: 29236211 PMCID: PMC5956048 DOI: 10.1007/s13318-017-0453-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Background and Objectives Acute kidney injury (AKI) is frequently observed after heart transplantation and is associated with morbidity and mortality. However, many confounding factors also contribute to the development of AKI in heart transplants. We hypothesized that supratherapeutic whole-blood tacrolimus trough concentrations are associated with AKI. Methods In a retrospective observational cohort from April 2005 to December 2012, all adult heart transplantation patients were included. AKI was assessed in the first 2 weeks after transplantation as classified by the Kidney Disease Improving Global Outcomes Network (KDIGO). Whole-blood tacrolimus trough concentrations were determined from day 1 to day 14 and at 1, 3, 6 and 12 months post-transplantation. The therapeutic range was 9 to 15 ng/ml in the first 2 months and tapered to 5–8 ng/ml thereafter. The relationship between supratherapeutic tacrolimus trough concentrations and AKI was evaluated. The impact of various potentially confounding factors on tacrolimus concentrations and AKI was considered. Results We included 110 patients. AKI occurred in 57% of patients in the first week. Recovery from AKI was seen in 24%. The occurrence of chronic kidney disease (CKD) was 19% at 1 year. Whole-blood tacrolimus trough concentrations were often supratherapeutic and, despite correction for confounding factors, independently associated with AKI (OR 1.66; 95% CI 1.20–2.31). Conclusions Supratherapeutic whole-blood tacrolimus trough concentrations are independently associated with the development of AKI in adult heart transplantation patients. More stringent dosing of tacrolimus early after transplantation may be critical in preserving the kidney function. Electronic supplementary material The online version of this article (10.1007/s13318-017-0453-7) contains supplementary material, which is available to authorized users.
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29
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Acuna SA. Etiology of increased cancer incidence after solid organ transplantation. Transplant Rev (Orlando) 2018; 32:218-224. [PMID: 30017342 DOI: 10.1016/j.trre.2018.07.001] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Revised: 06/28/2018] [Accepted: 07/05/2018] [Indexed: 01/15/2023]
Abstract
Over the past decades, there has been an encouraging increase in survival after solid organ transplantation. However, with longer life spans, more transplant recipients are at risk of dying with functioning grafts from illnesses such as cancer and cardiovascular conditions. Malignancy has emerged as an important cause of death in transplant recipients and is expected to become the leading cause of death in transplanted patients within the next decade. While it is known that solid organ transplant recipients have a three to five-fold increased risk of developing cancer compared with the general population, the mechanisms that lead to the observed excess risk in transplant recipients are less clear. This review explores the etiology of the increased cancer incidence in solid organ transplant including the effect of immunosuppressants on immunosurveillance and activation of oncogenic viruses, and carcinogenic effects of these medications; the role of chronic stimulation of the immune system on the development of cancer; and the impact of pre-existing cancer risk factors and factors related to end-stage organ disease on the cancer excess incidence in solid organ transplant recipients.
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Affiliation(s)
- Sergio A Acuna
- Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada; Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Canada; Department of Surgery, St. Michael's Hospital, Toronto, Canada; Division of General Surgery, Department of Surgery, University of Toronto, Toronto, Canada.
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30
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Schweiger M, Zuckermann A, Beiras-Fernandez A, Berchtolld-Herz M, Boeken U, Garbade J, Hirt S, Richter M, Ruhpawar A, Schmitto JD, Schönrath F, Schramm R, Schulz U, Wilhelm MJ, Barten MJ. A Review of Induction with Rabbit Antithymocyte Globulin in Pediatric Heart Transplant Recipients. Ann Transplant 2018; 23:322-333. [PMID: 29760372 PMCID: PMC6248300 DOI: 10.12659/aot.908243] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Pediatric heart transplantation (pHTx) represents only a small proportion of cardiac transplants. Due to these low numbers, clinical data relating to induction therapy in this special population are far less extensive than for adults. Induction is used more widely in pHTx than in adults, mainly because of early steroid withdrawal or complete steroid avoidance. Antithymocyte globulin (ATG) is the most frequent choice for induction in pHTx, and rabbit antithymocyte globulin (rATG, Thymoglobulin®) (Sanofi Genzyme) is the most widely-used ATG preparation. In the absence of large, prospective, blinded trials, we aimed to review the current literature and databases for evidence regarding the use, complications, and dosages of rATG. Analyses from registry databases suggest that, overall, ATG preparations are associated with improved graft survival compared to interleukin-2 receptor antagonists. Advantages for the use of rATG have been shown in low-risk patients given tacrolimus and mycophenolate mofetil in a steroid-free regimen, in sensitized patients with pre-formed alloantibodies and/or a positive donor-specific crossmatch, and in ABO-incompatible pHTx. Registry and clinical data have indicated no increased risk of infection or post-transplant lymphoproliferative disorder in children given rATG after pHTx. A total rATG dose in the range 3.5–7.5 mg/kg is advisable.
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Affiliation(s)
- Martin Schweiger
- Department of Cardiac Surgery, Children's Hospital, Zürich, Switzerland
| | - Andreas Zuckermann
- Department of Cardiac Surgery, Medical University of Vienna, Vienna, Austria
| | | | | | - Udo Boeken
- Department of Cardiovascular Surgery, Heinrich Heine University, Düsseldorf, Germany
| | - Jens Garbade
- Department of Cardiac Surgery, University Hospital Leipzig, Leipzig, Germany
| | - Stephan Hirt
- Department of Cardiac and Thoracic Surgery, University of Regensburg, Regensburg, Germany
| | | | - Arjang Ruhpawar
- Cardiac Surgery Clinic, University of Heidelberg, Heidelberg, Germany
| | - Jan Dieter Schmitto
- Department of Cardiac, Thoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany
| | - Felix Schönrath
- Department of Cardiothoracic and Vascular Surgery, German Heart Center Berlin, and DZHK (German Center for Cardiovascular Research), Berlin, Germany
| | - Rene Schramm
- Clinic of Cardiac Surgery, Ludwig Maximilian University, Munich, Germany
| | - Uwe Schulz
- Clinic for Thoracic and Cardiovascular Surgery, Heart and Diabetes Center NRW, Ruhr-University Bochum, Bad Oeynhausen, Germany
| | - Markus J Wilhelm
- Clinic for Cardiovascular Surgery, University Hospital Zürich, Zürich, Switzerland
| | - Markus J Barten
- University Heart Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany
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Abstract
Immunosuppressive therapy is arguably the most important component of medical care after lung transplantation. The goal of immunosuppression is to prevent acute and chronic rejection while maximizing patient survival and long-term allograft function. However, the benefits of immunosuppressive therapy must be balanced against the side effects and major toxicities of these medications. Immunosuppressive agents can be classified as induction agents, maintenance therapies, treatments for acute rejection and chronic rejection and antibody directed therapies. Although induction therapy remains an area of controversy in lung transplantation, it is still used in the majority of transplant centers. On the other hand, maintenance immunosuppression is less contentious; but, unfortunately, since the creation of three-drug combination therapy, including a glucocorticoid, calcineurin inhibitor and anti-metabolite, there have been relatively modest improvements in chronic maintenance immunosuppressive regimens. The presence of HLA antibodies in transplant candidates and development of de novo antibodies after transplantation remain a major therapeutic challenge before and after lung transplantation. In this chapter we review the medications used for induction and maintenance immunosuppression along with their efficacy and side effect profiles. We also review strategies and evidence for HLA desensitization prior to lung transplantation and management of de novo antibody formation after transplant. Finally, we review immune tolerance and the future of lung transplantation to limit the toxicities of conventional immunosuppressive therapy.
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Affiliation(s)
- Luke J Benvenuto
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Columbia University Medical Center, New York, USA
| | - Michaela R Anderson
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Columbia University Medical Center, New York, USA
| | - Selim M Arcasoy
- Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, Columbia University Medical Center, New York, USA
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32
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Mok CC. Calcineurin inhibitors in systemic lupus erythematosus. Best Pract Res Clin Rheumatol 2017; 31:429-438. [PMID: 29224682 DOI: 10.1016/j.berh.2017.09.010] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2017] [Revised: 08/06/2017] [Accepted: 09/02/2017] [Indexed: 01/14/2023]
Abstract
The calcineurin inhibitors (CNIs) belong to a group of immunosuppressive agents that block T-cell activation through the suppression of the calcium/calcimodulin-dependent phosphatase calcineurin. Agents such as cyclosporine A (CSA) and tacrolimus (TAC) have long been used in patients with systemic lupus erythematosus (SLE). TAC is preferred to CSA in SLE because of the lower frequency of cosmetic, hypertensive and dyslipidemic adverse effects. Recent randomised controlled trials have demonstrated noninferiority of TAC to mycophenolate mofetil (MMF) or cyclophosphamide (CYC) for induction therapy of lupus nephritis. Low-dose combination of TAC and MMF has also been shown to outperform CYC pulses in inducing remission of lupus nephritis in Chinese patients. TAC does not affect fertility and is relatively safe in pregnancy. In SLE patients who are intolerant or refractory to conventional immunosuppressives, or where contraindications to other immunosuppressive agents exist, TAC is an alternative option. However, the therapeutic window of TAC is narrow, and drug level monitoring is required to ensure drug exposure and minimise toxicities. Current evidence of TAC in lupus nephritis is limited to 6 months, and its long-term safety as maintenance therapy of SLE is yet to be determined. Newer chemical analogues of CNIs, such as voclosporin, with less variable plasma concentration are being tested in lupus nephritis.
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Affiliation(s)
- Chi Chiu Mok
- Department of Medicine, Tuen Mun Hospital, Tsing Chung Koon Road, New Territories, Hong Kong, China.
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Helal M, Obada M, Elrazek WA, Safan M, El-Hakim TA, El-Said H. Effect of ABCB1 (3435C>T) and CYP3A5 (6986A>G) genes polymorphism on tacrolimus concentrations and dosage requirements in liver transplant patients. EGYPTIAN JOURNAL OF MEDICAL HUMAN GENETICS 2017. [DOI: 10.1016/j.ejmhg.2016.10.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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Vega E, Schroder J, Nicoara A. Postoperative management of heart transplantation patients. Best Pract Res Clin Anaesthesiol 2017; 31:201-213. [PMID: 29110793 DOI: 10.1016/j.bpa.2017.06.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Revised: 06/01/2017] [Accepted: 06/16/2017] [Indexed: 01/17/2023]
Abstract
Heart transplant recipients are at risk for a number of post-transplantation complications such as graft dysfunction, rejection, and infection. The rates of many complications are decreasing over time, and prognosis is improving. However, these patients continue to experience significant morbidity and mortality. This review focuses on the optimal management of heart transplant recipients in the postoperative period, based on current knowledge. More information is needed about the best ways to predict, prevent, and treat primary graft dysfunction, right ventricular failure, and cellular and antibody-mediated rejection.
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Affiliation(s)
- Eleanor Vega
- Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA.
| | - Jacob Schroder
- Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA.
| | - Alina Nicoara
- Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA.
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35
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Helmschrott M, Rivinius R, Bruckner T, Katus HA, Doesch AO. Renal function in heart transplant patients after switch to combined mammalian target of rapamycin inhibitor and calcineurin inhibitor therapy. DRUG DESIGN DEVELOPMENT AND THERAPY 2017; 11:1673-1680. [PMID: 28652705 PMCID: PMC5472407 DOI: 10.2147/dddt.s135503] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
BACKGROUND A calcineurin inhibitor (CNI)-based immunosuppression combined with mammalian target of rapamycin inhibitors (mTORs) seems to be attractive in patients after heart transplantation (HTX) in special clinical situations, for example, in patients with adverse drug effects of prior immunosuppression. Previous studies in patients after HTX detected advantageous effects regarding renal function of a tacrolimus (TAC)-based vs cyclosporine-A (CSA)-based immunosuppression (in combination with mycophenolate mofetil). However, data regarding renal function after HTX in mTOR/CNI patients remain limited. AIM Primary end point of the present study was to analyze renal function in HTX patients 1 year after switch to an mTOR/CNI-based immunosuppression. METHODS Data of 80 HTX patients after change to mTOR/CNI-based immunosuppression were retrospectively analyzed. Renal function was assessed by measured serum creatinine and by estimated glomerular filtration rate (eGFR) calculated from Modification of Diet in Renal Disease equation. RESULTS Twenty-nine patients received mTOR/CSA-based treatment and 51 patients received mTOR/TAC-based therapy. At time of switch and at 1-year follow-up, serum creatinine and eGFR did not differ significantly between both study groups (all P=not statistically significant). Analysis of variances with repeated measurements detected a similar change of renal function in both study groups. CONCLUSION The present study detected no significant differences between both mTOR/CNI study groups, indicating a steady state of renal function in HTX patients after switch of immunosuppressive regimen.
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Affiliation(s)
| | | | - Thomas Bruckner
- Institute for Medical Biometry and Informatics, University of Heidelberg, Heidelberg, Germany
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Ge J, Wang J, Zhao H, Li K, Jing Y, Li G. Impact of FOXP3 Polymorphisms on the Blood Level of Tacrolimus in Renal Transplant Recipients. Transplant Proc 2017; 48:1962-7. [PMID: 27569929 DOI: 10.1016/j.transproceed.2016.04.016] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Revised: 04/11/2016] [Accepted: 04/27/2016] [Indexed: 12/26/2022]
Abstract
INTRODUCTION Tacrolimus is an immunosuppressive medication for organ transplantation. FOXP3(+) T regulatory cells (Tregs) play roles in suppression of rejection and induction of graft tolerance. This study aimed to evaluate the correlation between the polymorphism of FOXP3 and the blood level of tacrolimus in renal transplant recipients. METHODS This retrospective study included 100 renal transplant recipients receiving tacrolimus treatment and 100 healthy control subjects. Genotyping for FOXP3 rs3761547 AA, AG, GG, rs3761548 AA, AC, CC and rs223236 AA, AG, GG was performed. Concentrations of tacrolimus, creatinine, and urea nitrogen levels in blood were measured. RESULTS Frequencies of genotypes of FOXP3 rs3761548 AA, AC, and CC, rs3761547 AA, AG, GG and rs 223236 AA, AG, GG in renal transplant recipients were similar to those in normal people. The blood level of tacrolimus in recipients with rs3761548 CC was significantly higher than that in recipients with rs3761548 AA and AC (P < .001). No difference in the blood level of tacrolimus was found in recipients with different genotypes of rs3761547 and rs223236. Compared to rs3761548 AA and AC groups, there was no difference of Modification of Diet in Renal Disease (MDRD) glomerular filtration rate and the level of blood urea nitrogen before transplantation; however, these 2 parameters were significantly improved after transplantation in the rs3761548 CC group. The level of tacrolimus was correlated positively with MDRD glomerular filtration rate and negatively with the blood urea nitrogen level in recipients with rs3761548 CC genotype after transplantation. CONCLUSIONS Our study identified a new relationship between FOXP3 rs3761548 and the blood level of tacrolimus. These results suggest that the polymorphism of FOXP3 may affect tacrolimus pharmacokinetics.
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Affiliation(s)
- J Ge
- Department of Breast Surgery and Key Laboratory of Breast Cancer Prevention, Tianjin Medical University Cancer Institute and Hospital, Tianjin, P. R. China
| | - J Wang
- Basic Medical College, Tianjin Medical University, Tianjin, P. R. China
| | - H Zhao
- Department of Breast Surgery and Key Laboratory of Breast Cancer Prevention, Tianjin Medical University Cancer Institute and Hospital, Tianjin, P. R. China
| | - K Li
- Basic Medical College, Tianjin Medical University, Tianjin, P. R. China
| | - Y Jing
- Basic Medical College, Tianjin Medical University, Tianjin, P. R. China
| | - G Li
- Basic Medical College, Tianjin Medical University, Tianjin, P. R. China.
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Bogossian H, Frommeyer G, Ninios I, Bandorski D, Seyfarth M, Matzaroglou C, Lemke B, Eckardt L, Zarse M, Kafchitsas K. Expression of NO Synthase Under Medication with Cyclosporine A, Mycophenolate Mofetil, and Tacrolimus during Development of Transplant Vasculopathy on Rat Cardiac Allograft. Cardiovasc Ther 2017; 34:183-90. [PMID: 26924260 DOI: 10.1111/1755-5922.12181] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
OBJECTIVE The transplant vasculopathy as a sign of chronic graft rejection affects both the epicardial and the intramyocardial arteries of the graft. This is at least partially mediated by NO synthases. The aim of this study was to assess possible protective effects of cyclosporine A (CsA), tacrolimus (FK506), and mycophenolate mofetil (MMF) on the expression of NO synthases in an experimental transplant rat model. AIMS Heart transplantation was performed in 322 rats. These were randomly assigned to four equal groups (control, CsA, FK506, MMF). Recipients were monitored up to 60 days after transplantation, while transplanted hearts were recovered at certain time points for analysis. Expression and staining intensity for endothelial nitric oxide synthases (e-nos) and inducible nitric oxide synthases (i-nos) were analyzed in epicardial and intramyocardial vessels in each group. RESULTS All employed drugs led to a significant reduction of expression or staining intensity of i-nos and e-nos. MMF was most effective in reduction in expression of both NO synthases. CONCLUSIONS These results imply that all described drugs prevent endothelial impairment induced by toxicity of NO and thereby prevent transplant vasculopathy. MMF seems to be the most effective drug.
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Affiliation(s)
- Harilaos Bogossian
- Märkische Kliniken GmbH, Department of Cardiology and Angiology, Klinikum Lüdenscheid, Ludenscheid, Germany.,Department of Cardiology, Witten / Herdecke University, Witten, Germany
| | - Gerrit Frommeyer
- Division of Electrophysiology, Department of Cardiovascular Medicine, University of Münster, Münster, Germany
| | - Ilias Ninios
- Märkische Kliniken GmbH, Department of Cardiology and Angiology, Klinikum Lüdenscheid, Ludenscheid, Germany
| | - Dirk Bandorski
- Märkische Kliniken GmbH, Department of Cardiology and Angiology, Klinikum Lüdenscheid, Ludenscheid, Germany
| | - Melchior Seyfarth
- Department of Cardiology, Helios Klinikum Wuppertal, Wuppertal, Germany.,Department of Cardiology, Witten / Herdecke University, Witten, Germany
| | | | - Bernd Lemke
- Märkische Kliniken GmbH, Department of Cardiology and Angiology, Klinikum Lüdenscheid, Ludenscheid, Germany
| | - Lars Eckardt
- Division of Electrophysiology, Department of Cardiovascular Medicine, University of Münster, Münster, Germany
| | - Markus Zarse
- Märkische Kliniken GmbH, Department of Cardiology and Angiology, Klinikum Lüdenscheid, Ludenscheid, Germany.,Department of Cardiology, Witten / Herdecke University, Witten, Germany
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Rower JE, Stockmann C, Linakis MW, Kumar SS, Liu X, Korgenski EK, Sherwin CMT, Molina KM. Predicting tacrolimus concentrations in children receiving a heart transplant using a population pharmacokinetic model. BMJ Paediatr Open 2017; 1:e000147. [PMID: 29177199 PMCID: PMC5699789 DOI: 10.1136/bmjpo-2017-000147] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
OBJECTIVE Immunosuppressant therapy plays a pivotal role in transplant success and longevity. Tacrolimus, a primary immunosuppressive agent, is well known to exhibit significant pharmacological interpatient and intrapatient variability. This variability necessitates the collection of serial trough concentrations to ensure that the drug remains within therapeutic range. The objective of this study was to build a population pharmacokinetic (PK) model and use it to determine the minimum number of trough samples needed to guide the prediction of an individual's future concentrations. DESIGN SETTING AND PATIENTS Retrospective data from 48 children who received tacrolimus as inpatients at Primary Children's Hospital in Salt Lake City, Utah were included in the study. Data were collected within the first 6 weeks after heart transplant. OUTCOME MEASURES Data analysis used population PK modelling techniques in NONMEM. Predictive ability of the model was determined using median prediction error (MPE, a measure of bias) and median absolute prediction error (MAPE, a measure of accuracy). Of the 48 children in the study, 30 were used in the model building dataset, and 18 in the model validation dataset. RESULTS Concentrations ranged between 1.5 and 37.7 μg/L across all collected data, with only 40% of those concentrations falling within the targeted concentration range (12 to 16 μg/L). The final population PK model contained the impact of age (on volume), creatinine clearance (on elimination rate) and fluconazole use (on elimination rate) as covariates. Our analysis demonstrated that as few as three concentrations could be used to predict future concentrations, with negligible bias (MPE (95% CI)=0.10% (-2.9% to 3.7%)) and good accuracy (MAPE (95% CI)=24.1% (19.7% to 27.7%)). CONCLUSIONS The use of PK in dose guidance has the potential to provide significant benefits to clinical care, including dose optimisation during the early stages of therapy, and the potential to limit the need for frequent drug monitoring.
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Affiliation(s)
- Joseph E Rower
- Department of Pediatrics, Division of Clinical Pharmacology, University of Utah School of Medicine, Salt Lake City, Utah, USA
| | - Chris Stockmann
- Department of Pediatrics, Division of Clinical Pharmacology, University of Utah School of Medicine, Salt Lake City, Utah, USA
| | - Matthew W Linakis
- Department of Pediatrics, Division of Clinical Pharmacology, University of Utah School of Medicine, Salt Lake City, Utah, USA
| | - Shaun S Kumar
- Department of Pediatrics, Division of Clinical Pharmacology, University of Utah School of Medicine, Salt Lake City, Utah, USA
| | - Xiaoxi Liu
- Department of Pediatrics, Division of Clinical Pharmacology, University of Utah School of Medicine, Salt Lake City, Utah, USA
| | - E Kent Korgenski
- Pediatric Clinical Program, Intermountain Healthcare, Salt Lake City, Utah, USA
| | - Catherine M T Sherwin
- Department of Pediatrics, Division of Clinical Pharmacology, University of Utah School of Medicine, Salt Lake City, Utah, USA.,Department of Pharmacology and Toxicology, University of Utah College of Pharmacy, Salt Lake City, Utah, USA
| | - Kimberly M Molina
- Primary Children's Hospital, Intermountain Healthcare, Salt Lake City, Utah, USA.,Department of Pediatrics, Division of Cardiology, University of Utah School of Medicine, Salt Lake City, Utah, USA
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Abstract
Major neurologic morbidity, such as seizures and encephalopathy, complicates 20-30% of organ and stem cell transplantation procedures. The majority of these disorders occur in the early posttransplant period, but recipients remain at risk for opportunistic infections and other nervous system disorders for many years. These long-term risks may be increasing as acute survival increases, and a greater number of "sicker" patients are exposed to long-term immunosuppression. Drug neurotoxicity accounts for a significant proportion of complications, with posterior reversible leukoencephalopathy syndrome, primarily associated with calcineurin inhibitors (i.e., cyclosporine and tacrolimus), being prominent as a cause of seizures and neurologic deficits. A thorough evaluation of any patient who develops neurologic symptoms after transplantation is mandatory, since reversible and treatable conditions could be found, and important prognostic information can be obtained.
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Affiliation(s)
- R Dhar
- Division of Neurocritical Care, Department of Neurology, Washington University, St. Louis, MO, USA.
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NG Hoi-Yan A, Mok CC. Therapeutic Drug Monitoring in Rheumatic Diseases. HONG KONG BULLETIN ON RHEUMATIC DISEASES 2016. [DOI: 10.1515/hkbrd-2016-0009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Abstract
The ultimate goal of treating rheumatic disease is to achieve rapid suppression of inflammation, while at the same time minimizing the toxicities from rheumatic drugs. Different patients have different individual pharmacokinetics that can affect the drug level. Moreover, different factors, such as renal function, age or even different underlying diseases, can affect the drug level. Therefore, giving the same dosage of drugs to different patients may result in different drug levels. This article will review the usefulness of therapeutic drug monitoring in maximizing drug efficacy, while reducing the risk of toxicities in Hydroxychloroquine, Mycophenolate Mofetil, Tacrolimus and Tumor Necrosis Factor inhibitors (TNF Inhibitors).
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Affiliation(s)
| | - Chi Chiu Mok
- Department of Medicine, Tuen Mun Hospital, Hong Kong instead of “Deputy Chief of Service” , Tuen Mun , Hong Kong
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Systematic Review and Meta-Analysis of Tacrolimus versus Ciclosporin as Primary Immunosuppression After Liver Transplant. PLoS One 2016; 11:e0160421. [PMID: 27812112 PMCID: PMC5094765 DOI: 10.1371/journal.pone.0160421] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2015] [Accepted: 07/19/2016] [Indexed: 01/24/2023] Open
Abstract
Background and Aims Several meta-analyses comparing ciclosporin with tacrolimus have been conducted since the 1994 publication of the tacrolimus registration trials, but most captured data from randomized controlled trials (RCTs) predating recent improvements in waiting list prioritization, induction protocols and concomitant medications. The present study comprised a systematic review and meta-analysis of ciclosporin and tacrolimus in liver transplant recipients using studies published since January 2000. Methods Searches of PubMed, the Cochrane Library and EMBASE identified RCTs of tacrolimus and ciclosporin as the immunosuppressant in adult primary liver transplant recipients, published between January 2000 and August 6, 2014. A random effects meta-analysis was conducted to evaluate the relative risk of death, graft loss, acute rejection (AR), new-onset diabetes after transplantation (NODAT) and hypertension with tacrolimus relative to ciclosporin at 12 months. Results The literature search identified 11 RCTs comparing ciclosporin with tacrolimus. Relative to ciclosporin, tacrolimus was associated with significantly improved outcomes in terms of patient mortality (risk ratio [RR] with ciclosporin of 1.26; 95% confidence interval [95%CI] 1.01–1.58). Tacrolimus was superior to ciclosporin in terms of hypertension (RR with ciclosporin 1.26; 95%CI 1.07–1.47), but inferior in terms of NODAT (RR with ciclosporin 0.60; 95%CI 0.47–0.77). There were no significant differences between ciclosporin and tacrolimus in terms of graft loss or AR. Conclusions Meta-analysis of RCTs published since 2000 showed tacrolimus to be superior to ciclosporin in terms of patient mortality and hypertension, while ciclosporin was superior in terms of NODAT. No significant differences were identified in terms of graft loss or AR. These findings provide further evidence supporting the use of tacrolimus as the cornerstone of immunosuppressive therapy in liver transplant recipients.
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Mok CC. Pro: The use of calcineurin inhibitors in the treatment of lupus nephritis. Nephrol Dial Transplant 2016; 31:1561-6. [PMID: 27591327 DOI: 10.1093/ndt/gfw289] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2016] [Accepted: 03/19/2016] [Indexed: 12/11/2022] Open
Abstract
Renal disease in systemic lupus erythematosus (SLE) carries significant morbidity and mortality. Cyclophosphamide (CYC)- and mycophenolate mofetil (MMF)-based induction regimens are not ideal in terms of efficacy and toxicity. The adverse effects of CYC, such as infection risk, infertility, urotoxicity and oncogenicity, limit its use in lupus nephritis. Although MMF is non-inferior to CYC as induction therapy and has reduced gonadal toxicity and oncogenic potential, meta-analyses of clinical trials do not show a lower rate of infective and gastrointestinal complications. Tacrolimus (TAC) has recently been shown to have equal efficacy to either MMF or CYC for inducing remission of lupus nephritis. A low-dose combination of MMF and TAC appears to be more effective than intravenous CYC pulses in Chinese patients, and has potential to replace the more toxic CYC regimens in high-risk subgroups. TAC may be considered as another non-CYC alternative for induction therapy of lupus nephritis and in those with refractory disease or intolerance to CYC or MMF. TAC has no negative effect on fertility in younger women, and unlike MMF and CYC, it is safe in pregnancy. However, TAC has a narrow therapeutic window and drug level monitoring is required to ensure drug exposure and minimize acute toxicities. Current evidence for the efficacy of TAC in lupus nephritis is limited to 6 months and the incidence of renal flare after discontinuation of therapy or switching to azathioprine appears to be higher than other induction agents. Long-term data and the incidence of chronic nephrotoxicity of TAC as maintenance therapy in lupus nephritis are currently lacking and further prospective trials are needed to address these issues.
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Affiliation(s)
- Chi Chiu Mok
- Department of Medicine, Tuen Mun Hospital, Hong Kong, SAR, China
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Impact of Insurance Type on Initial Rejection Post Heart Transplant. Heart Lung Circ 2016; 26:164-171. [PMID: 27475258 DOI: 10.1016/j.hlc.2016.05.123] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2016] [Revised: 05/14/2016] [Accepted: 05/28/2016] [Indexed: 11/24/2022]
Abstract
BACKGROUND Heart transplantation allocation is often restricted from patients with low socioeconomic status (SES) due to concern for worse outcomes. We hypothesised that comorbidities would have a greater impact on risk of severe rejection post-orthotopic heart transplant than would Medicaid insurance and Median Household Income (MHI). METHODS A retrospective study of 171 patients who underwent orthotopic heart transplant between 7/1999-11/2013 at our facility were followed until 9/2014 for rejection hospitalisations or death. Survival and multivariable analyses with adjustment for age, race, and gender were performed to estimate the risk of severe cellular rejection, ≥2r (hazard ratio [HR], 95% confidence interval [CI]). RESULTS Eighteen per cent of patients had Medicaid, and 72% of patients had low or medium MHI. Severe rejection occurred in 23% of patients. In the univariable analysis, Medicaid and diabetes were associated with increased risk of rejection while age >60 years, Caucasian race, and male sex were associated with reduced risk [Medicaid 2.32(1.20,4.51), diabetes 2.49(1.09,5.69), age 0.41(0.20,0.84), Caucasian 0.44(0.21,0.93), male 0.49(0.26,0.92)]. Median Household Income had no correlation [MHI 0.79(0.51,1.23)]. In the multivariable adjusted model, Medicaid was not associated with rejection [1.65(0.79,3.41)]; diabetes was strongly associated with risk of severe rejection [3.9(1.59,9.39)], and age >60 years was associated with risk reduction [0.42(0.20,0.82)]. CONCLUSIONS Medicaid insurance and MHI were not associated with increased risk of severe cellular rejection requiring hospitalisation post-orthotopic heart transplant in the adjusted model. Rather the presence of diabetes and age ≤60 years were associated with increased risk.
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Mok CC. Therapeutic monitoring of the immuno-modulating drugs in systemic lupus erythematosus. Expert Rev Clin Immunol 2016; 13:35-41. [PMID: 27417340 DOI: 10.1080/1744666x.2016.1212659] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Chi Chiu Mok
- Department of Medicine, Tuen Mun Hospital, Hong Kong, China
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Gullestad L, Eiskjaer H, Gustafsson F, Riise GC, Karason K, Dellgren G, Rådegran G, Hansson L, Gude E, Bjørtuft Ø, Jansson K, Schultz HH, Solbu D, Iversen M. Long-term outcomes of thoracic transplant recipients following conversion to everolimus with reduced calcineurin inhibitor in a multicenter, open-label, randomized trial. Transpl Int 2016; 29:819-29. [DOI: 10.1111/tri.12783] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Revised: 01/20/2016] [Accepted: 04/07/2016] [Indexed: 12/24/2022]
Affiliation(s)
- Lars Gullestad
- Department of Cardiology; Oslo University Hospital Rikshospitalet; Oslo Norway
- Faculty of Medicine; K.G. Jebsen Cardiac Research Centre and Center for Heart Failure Research; University of Oslo; Oslo Norway
| | - Hans Eiskjaer
- Department of Cardiology; Aarhus University Hospital; Skejby Aarhus Denmark
| | - Finn Gustafsson
- Department of Cardiology; Rigshospitalet; Copenhagen Denmark
| | - Gerdt C. Riise
- Department of Respiratory Medicine; Sahlgrenska University Hospital; Gothenburg Sweden
| | - Kristjan Karason
- Department of Cardiology and Transplant Institute; Sahlgrenska University Hospital; Gothenburg Sweden
| | - Göran Dellgren
- Department of Cardiology and Transplant Institute; Sahlgrenska University Hospital; Gothenburg Sweden
| | - Göran Rådegran
- Department of Clinical Sciences Lund, Cardiology; Lund University and the Section for Heart Failure and Valvular Disease; Skåne University Hospital; Lund Sweden
| | - Lennart Hansson
- Department of Respiratory Medicine; Lund University Hospital and Skåne University Hospital; Lund Sweden
| | - Einar Gude
- Department of Cardiology; Oslo University Hospital Rikshospitalet; Oslo Norway
- Faculty of Medicine; K.G. Jebsen Cardiac Research Centre and Center for Heart Failure Research; University of Oslo; Oslo Norway
| | - Øystein Bjørtuft
- Department of Respiratory Medicine; Oslo University Hospital Rikshospitalet; Oslo Norway
| | - Kjell Jansson
- Department of Cardiology, Heart Center; University Hospital; Linkoping Sweden
| | - Hans Henrik Schultz
- Division of Lung Transplantation; Department of Cardiology; Rigshospitalet; Copenhagen Denmark
| | | | - Martin Iversen
- Division of Lung Transplantation; Department of Cardiology; Rigshospitalet; Copenhagen Denmark
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Abstract
Renal involvement in systemic lupus erythematosus (SLE) carries substantial morbidity and mortality. Conventional immunosuppressive agents (cyclophosphamide and azathioprine) have suboptimal efficacy and substantial toxicity. Mycophenolate mofetil has emerged as an alternative agent for both induction and maintenance therapy in lupus nephritis because of its reduced gonadal toxicity, despite its failure to demonstrate superiority over cyclophosphamide in pivotal studies. The calcineurin inhibitor tacrolimus has equivalent efficacy to cyclophosphamide and mycophenolate mofetil for inducing remission of lupus nephritis. Although rituximab has shown promise in refractory lupus nephritis, combining rituximab with mycophenolate mofetil as initial therapy offers no additional benefit. Considerable interethnic variation is evident in the efficacy and tolerability of the various immunosuppressive regimens, which necessitates individualized treatment and comparison of the efficacy of new regimens across different ethnic groups. For example, low-dose combinations of tacrolimus and mycophenolate mofetil seem to be more effective than pulse cyclophosphamide as induction therapy in Chinese patients. The same regimen has also been used successfully to treat refractory proliferative and membranous lupus nephritis in patients of various ethnic groups. Finally, novel serum and urinary biomarkers are being validated for diagnosis, prognostic stratification and early recognition of flares in lupus nephritis.
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Affiliation(s)
- C C Mok
- Department of Medicine, Tuen Mun Hospital, 23 Tsing Chung Koon Road, New Territories, Hong Kong SAR, China
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48
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Mok CC, Ying KY, Yim CW, Siu YP, Tong KH, To CH, Ng WL. Tacrolimus versus mycophenolate mofetil for induction therapy of lupus nephritis: a randomised controlled trial and long-term follow-up. Ann Rheum Dis 2016; 75:30-6. [PMID: 25550339 DOI: 10.1136/annrheumdis-2014-206456] [Citation(s) in RCA: 139] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2014] [Accepted: 12/07/2014] [Indexed: 12/17/2022]
Abstract
OBJECTIVE To compare the efficacy of tacrolimus (TAC) and mycophenolate mofetil (MMF) for the initial therapy of lupus nephritis (LN). STUDY DESIGN This is an open randomised controlled parallel group study. METHODS Adult patients with biopsy-confirmed active LN (class III/IV/V) were randomised to receive prednisolone (0.6 mg/kg/day for 6 weeks and tapered) in combination with either TAC (0.06-0.1 mg/kg/day) or MMF (2-3 g/day) for 6 months. Good responders were shifted to azathioprine for maintenance. The primary outcome was the rate of complete renal response (CR) at 6 months and the secondary outcomes included partial renal response, renal flares and decline of renal function over time. RESULTS 150 patients (92% women; aged 35.5±12.8 years; 81% class III/IV) were randomised (76 MMF, 74 TAC). At month 6, the rate of CR was 59% in the MMF and 62% in the TAC group (treatment difference: 3.0% (-12%, 18%); p=0.71). Major infective episodes occurred in 9.2% patients treated with MMF and in 5.4% patients treated with TAC (p=0.53). Maintenance therapy with azathioprine was given to 79% patients. After 60.8±26 months, proteinuric and nephritic renal flares developed in 24% and 18% of patients in the MMF group and 35% (p=0.12) and 27% (p=0.21) in the TAC group, respectively. The cumulative incidence of a composite outcome of decline of creatinine clearance by ≥30%, development of chronic kidney disease stage 4/5 or death was 21% in the MMF and 22% in the TAC group of patients (p=0.35). CONCLUSIONS TAC is non-inferior to MMF, when combined with prednisolone, for induction therapy of active LN. With azathioprine maintenance for 5 years, a non-significant trend of higher incidence of renal flares and renal function decline is observed with the TAC regimen. TRIAL REGISTRATION NUMBER Hospital Authority Research Ethics Committee Clinical Trial Registry (HARECCTR0500018; Hong Kong) and US ClinicalTrials.gov (NCT00371319).
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Affiliation(s)
- Chi Chiu Mok
- Department of Medicine, Tuen Mun Hospital, Hong Kong
| | - King Yee Ying
- Department of Medicine, Princess Margaret Hospital, Hong Kong
| | - Cheuk Wan Yim
- Department of Medicine, United Christian Hospital, Hong Kong
| | - Yui Pong Siu
- Department of Medicine, Tuen Mun Hospital, Hong Kong
| | - Ka Hang Tong
- Department of Medicine, Tuen Mun Hospital, Hong Kong
| | - Chi Hung To
- Department of Medicine, Tuen Mun Hospital, Hong Kong
| | - Woon Leung Ng
- Department of Medicine, United Christian Hospital, Hong Kong
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Aral CA, Dilber E, Aral K, Sarica Y, Sivrikoz ON. Management of Cyclosporine and Nifedipine-Induced Gingival Hyperplasia. J Clin Diagn Res 2015; 9:ZD12-5. [PMID: 26812935 DOI: 10.7860/jcdr/2015/14737.6974] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2015] [Accepted: 09/21/2015] [Indexed: 11/24/2022]
Abstract
Gingival enlargements modified by medications are becoming more common because of the increased use of inducing drugs, and may create speech, mastication, tooth eruption, periodontal, and aesthetic problems. We hereby present a case of a 54-year-old man with 12-month history of generalized gingival enlargement in the keratinized gingiva was referred to our clinic. The patient had a history of kidney transplant and was under medication of cyclosporine and nifedipine. After medical consultation, cyclosporine was changed to tacrolimus and nifedipine was changed to captopril. Gingivectomy was performed using a diode laser, and scaling and root planning were performed. At five months postoperative, the gingival enlargements relapsed and diode laser-assisted surgery was repeated. The patient was followed-up on second postoperatively at 18 months and no relapse was seen. Diode laser-assisted gingivectomy was found to be useful for coagulation during surgery and decreased postoperative bleeding. Recurrence risk of cyclosporine and nifedipine-induced gingival overgrowth is high, thus, there is a great need for prolonged care of patients following treatment and prosthetic restoration.
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Affiliation(s)
- Cüneyt Asim Aral
- Assistant Professor, Department of Periodontology, Faculty of Dentistry, Sifa University , Izmir, Turkey
| | - Erhan Dilber
- Assistant Professor, Department of Prosthetic Dentistry, Faculty of Dentistry, Sifa University , Izmir, Turkey
| | - Kübra Aral
- Assistant Professor, Department of Periodontology, Faculty of Dentistry, Sifa University , Izmir, Turkey
| | - Yagmur Sarica
- Research Assistant, Department of Histology & Embryology, Faculty of Medicine, Sifa University , Izmir, Turkey
| | - Oya Nermin Sivrikoz
- Assistant Professor, Department of Pathology, Faculty of Medicine, Sifa University , Izmir, Turkey
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Herbst S, Shah A, Mazon Moya M, Marzola V, Jensen B, Reed A, Birrell MA, Saijo S, Mostowy S, Shaunak S, Armstrong-James D. Phagocytosis-dependent activation of a TLR9-BTK-calcineurin-NFAT pathway co-ordinates innate immunity to Aspergillus fumigatus. EMBO Mol Med 2015; 7:240-58. [PMID: 25637383 PMCID: PMC4364943 DOI: 10.15252/emmm.201404556] [Citation(s) in RCA: 148] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Transplant recipients on calcineurin inhibitors are at high risk of invasive fungal infection. Understanding how calcineurin inhibitors impair fungal immunity is a key priority for defining risk of infection. Here, we show that the calcineurin inhibitor tacrolimus impairs clearance of the major mould pathogen Aspergillus fumigatus from the airway, by inhibiting macrophage inflammatory responses. This leads to defective early neutrophil recruitment and fungal clearance. We confirm these findings in zebrafish, showing an evolutionarily conserved role for calcineurin signalling in neutrophil recruitment during inflammation. We find that calcineurin–NFAT activation is phagocytosis dependent and collaborates with NF-κB for TNF-α production. For yeast zymosan particles, activation of macrophage calcineurin–NFAT occurs via the phagocytic Dectin-1–spleen tyrosine kinase pathway, but for A. fumigatus, activation occurs via a phagosomal TLR9-dependent and Bruton's tyrosine kinase-dependent signalling pathway that is independent of MyD88. We confirm the collaboration between NFAT and NF-κB for TNF-α production in primary alveolar macrophages. These observations identify inhibition of a newly discovered macrophage TLR9–BTK–calcineurin–NFAT signalling pathway as a key immune defect that leads to organ transplant-related invasive aspergillosis.
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Affiliation(s)
- Susanne Herbst
- Department of Infectious Diseases and Immunity, Imperial College London, London, UK
| | - Anand Shah
- Department of Infectious Diseases and Immunity, Imperial College London, London, UK
| | - Maria Mazon Moya
- MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, UK
| | - Vanessa Marzola
- Department of Infectious Diseases and Immunity, Imperial College London, London, UK
| | - Barbara Jensen
- Department of Infectious Diseases and Immunity, Imperial College London, London, UK
| | - Anna Reed
- Lung Transplant Unit, Royal Brompton and Harefield Hospital, London, UK
| | - Mark A Birrell
- National Heart and Lung Institute, Imperial College London, London, UK
| | - Shinobu Saijo
- Medical Mycology Research Centre, Chiba University, Chiba, Japan
| | - Serge Mostowy
- MRC Centre for Molecular Bacteriology and Infection, Imperial College London, London, UK
| | - Sunil Shaunak
- Department of Infectious Diseases and Immunity, Imperial College London, London, UK
| | - Darius Armstrong-James
- Department of Infectious Diseases and Immunity, Imperial College London, London, UK National Heart and Lung Institute, Imperial College London, London, UK
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