|
1
|
Nivya RM, Joy A. Neuroprotective propensity of N-(5-chloro-2-hydroxyphenyl)-2-(morpholin-4-yl-methyl) benzamide, an inventive calcineurin inhibitor, in biological models of Parkinson's disease. 3 Biotech 2025; 15:149. [PMID: 40321716 PMCID: PMC12048375 DOI: 10.1007/s13205-025-04314-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2025] [Accepted: 04/05/2025] [Indexed: 05/08/2025] Open
Abstract
The current work initially focused on the custom synthesis of ILB-162, an innovative calcineurin inhibitor, known chemically as N-(5-chloro-2-hydroxyphenyl)-2-(morpholin-4-yl-methyl) benzamide to get a yield of 25 mg with 90.73% purity and confirmed its significant calcineurin inhibitory potential in vitro having very low IC50 value (0.057 µM). Further assessment in L929 cells revealed low cytotoxicity (LD50 = 305.28 µg/mL) and the neuroprotection evaluated in SHSY 5Y cells induced with 6OHDA, identified 50 µg/mL as the optimal protective dose. The Parkinson's disease (PD) models in the current study were divided into three groups; Normal control (NC) without any treatment, Disease Control (DC) induced with chemical screens (6OHDA for SHSY 5Y cell line and Rotenone for C. elegans) and treated with ILB-162 group (induced cells treated with 50 µg/mL ILB-162), for accessing molecular as well as behavioral effects. In the Cell line models, ILB-162 treatment significantly reduced intracellular ROS as well as reversed α-synuclein overexpression, indicating its potential to reverse the molecular pathology underlying PD. Subsequent studies using C. elegans PD model assessed toxicity (LD50 = 1436.39 µM) comparable to in vitro observations and demonstrated the outstanding capability of ILB-162 to restore the dopamine-dependent behaviors which were disrupted in DC. These findings suggest that ILB-162 can be a promising therapeutic candidate against PD, justifying the further development.
Collapse
Affiliation(s)
- R. M. Nivya
- Research Scholar Affiliated to APJ Abdul Kalam Technological University of Kerala, Thiruvananthapuram, India
- Department of Biotechnology, Sahrdaya College of Engineering and Technology, Kodakara, Thrissur, 680684 Kerala India
| | - Amitha Joy
- Department of Biotechnology, Sahrdaya College of Engineering and Technology, Kodakara, Thrissur, 680684 Kerala India
| |
Collapse
|
|
2
|
Tsai CY, Lee CY, Chen JH, Chiang CK. Chronic Antibody-Mediated Rejection and Plasma Cell ER Stress: Opportunities and Challenges with Calcineurin Inhibitors. Int J Mol Sci 2025; 26:2711. [PMID: 40141353 PMCID: PMC11943340 DOI: 10.3390/ijms26062711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2024] [Revised: 03/10/2025] [Accepted: 03/14/2025] [Indexed: 03/28/2025] Open
Abstract
Chronic alloantibody-mediated rejection (cAMR) remains a major challenge in transplant immunology, with no FDA-approved targeted therapies currently available. Despite advancements in cellular immunosuppression, effective strategies to mitigate alloantibody-mediated rejection are still lacking. This review provides a comprehensive overview of transplant rejection with a particular focus on the pathophysiology and therapeutic landscape of cAMR. We highlight the role of plasma cell-driven alloantibody production and its susceptibility to endoplasmic reticulum (ER) stress, a pathway with potential for therapeutic intervention. Special attention is given to calcineurin inhibitors (CNIs), which, beyond their well-established T-cell inhibitory effects, exhibit differential impacts on ER stress and plasma cell viability. By delineating the mechanistic differences between cyclosporine and tacrolimus in regulating ER stress responses, we propose potential therapeutic implications for optimizing cAMR management. This review underscores the need for innovative strategies targeting plasma cell biology to improve long-term transplant outcomes.
Collapse
Affiliation(s)
- Ching-Yi Tsai
- Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei 100233, Taiwan; (C.-Y.T.); (J.-H.C.)
- Department of Medical Research, National Taiwan University Hospital, Taipei 100225, Taiwan
| | - Chih-Yuan Lee
- Department of Surgery, National Taiwan University Hospital, Taipei 100225, Taiwan;
- Organ Transplant Center, National Taiwan University Hospital, Taipei 100225, Taiwan
| | - Jia-Huang Chen
- Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei 100233, Taiwan; (C.-Y.T.); (J.-H.C.)
| | - Chih-Kang Chiang
- Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei 100233, Taiwan; (C.-Y.T.); (J.-H.C.)
- Department of Integrated Diagnostics & Therapeutics, National Taiwan University Hospital, Taipei 100225, Taiwan
| |
Collapse
|
|
3
|
Dash K, Mishra M. The tradeoff between the efficacy of calcineurin inhibitors: prevention of allograft rejection vs. post-transplant renal and cardiovascular complications. Crit Rev Toxicol 2025; 55:63-79. [PMID: 39807635 DOI: 10.1080/10408444.2024.2433631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Accepted: 11/19/2024] [Indexed: 01/16/2025]
Abstract
Solid organ transplantation has emerged as a crucial intervention in the field of medicine. During transplantation, our human body perceives the organ as an exogenous entity or graft, initiating an immune reaction to eliminate it. This immune response ultimately culminates in the rejection of the graft. So, to mitigate the possibility of graft rejection, implementing immune suppression is imperative. In this context, the utilization of calcineurin inhibitors (CNIs) assumes a pivotal role. Calcineurin inhibitors significantly preserve immunosuppression following solid organ transplantation. Calcineurin inhibitors have considerably improved short-term results in renal transplantation by reducing acute rejection rates. Concerning the limited therapeutic window of these medications, careful monitoring of pharmacological treatment and individual doses is required. However, a significant number of patients do experience CNI toxicity. Side effects of CNIs include renal failure, hypertension, respiratory disorders, gastrointestinal damage, gingivitis, and so on. Higher trough level of the drug causes acute nephrotoxicity, which is of three types: functional toxicity, tubular toxicity, and vascular toxicity. Acute nephrotoxicity, if untreated, leads to irreversible, progressive deterioration of allograft function, leading to chronic nephrotoxicity. Cardiovascular toxicity of CNIs includes atrial hypertension caused by vasoconstriction of the afferent arteriole, vascular remodeling, hypertrophy, dyslipidemia, and also the onset of diabetes. Such clinical complications further affect the patient's survivability and subjective well-being, possibly leading to graft loss. This review focuses on the most severe side effects of CNIs: renal and cardiovascular toxicity.
Collapse
Affiliation(s)
- Kalpanarani Dash
- Department of Life Sciences, Neural Developmental Biology Lab, National Institute of Technology, Rourkela, India
| | - Monalisa Mishra
- Department of Life Sciences, Neural Developmental Biology Lab, National Institute of Technology, Rourkela, India
| |
Collapse
|
|
4
|
Kim GR, Nam KH, Choi JM. Belatacept and regulatory T cells in transplantation: synergistic strategies for immune tolerance and graft survival. CLINICAL TRANSPLANTATION AND RESEARCH 2024; 38:326-340. [PMID: 39690903 PMCID: PMC11732762 DOI: 10.4285/ctr.24.0057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Revised: 11/22/2024] [Accepted: 11/28/2024] [Indexed: 12/19/2024]
Abstract
Calcineurin inhibitors (CNIs) have been a cornerstone in solid organ transplantation for many years; however, their prolonged use is linked to significant adverse effects, most notably nephrotoxicity. Belatacept, a modified version of cytotoxic T lymphocyte antigen-4 immunoglobulin with increased binding affinity for its ligand, has emerged as a viable alternative to traditional CNIs due to its lower toxicity profile. Despite these benefits, belatacept is associated with a higher rate of acute rejection, which presents a challenge for long-term graft survival. This review reevaluates the limitations of belatacept in achieving long-term acceptance of transplants and highlights the importance of regulatory T (Treg) cells in maintaining immune tolerance and preventing graft rejection. Additionally, it discusses the potential benefits of combining therapies that boost Treg cells with belatacept to increase the effectiveness of immunosuppression and improve graft outcomes.
Collapse
Affiliation(s)
- Gil-Ran Kim
- Department of Life Science, College of Natural Sciences, Hanyang University, Seoul, Korea
- Research Institute for Natural Sciences, Hanyang University, Seoul, Korea
| | - Kyung-Ho Nam
- Department of Life Science, College of Natural Sciences, Hanyang University, Seoul, Korea
| | - Je-Min Choi
- Department of Life Science, College of Natural Sciences, Hanyang University, Seoul, Korea
- Research Institute for Natural Sciences, Hanyang University, Seoul, Korea
- Hanyang Institute of Bioscience and Biotechnology, Hanyang University, Seoul, Korea
- Research Institute for Convergence of Basic Sciences, Hanyang University, Seoul, Korea
| |
Collapse
|
|
5
|
Houles T, Yoon SO, Roux PP. The expanding landscape of canonical and non-canonical protein phosphorylation. Trends Biochem Sci 2024; 49:986-999. [PMID: 39266329 DOI: 10.1016/j.tibs.2024.08.004] [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: 03/29/2024] [Revised: 08/01/2024] [Accepted: 08/14/2024] [Indexed: 09/14/2024]
Abstract
Protein phosphorylation is a crucial regulatory mechanism in cell signaling, acting as a molecular switch that modulates protein function. Catalyzed by protein kinases and reversed by phosphoprotein phosphatases, it is essential in both normal physiological and pathological states. Recent advances have uncovered a vast and intricate landscape of protein phosphorylation that include histidine phosphorylation and more unconventional events, such as pyrophosphorylation and polyphosphorylation. Many questions remain about the true size of the phosphoproteome and, more importantly, its site-specific functional relevance. The involvement of unconventional actors such as pseudokinases and pseudophosphatases adds further complexity to be resolved. This review explores recent discoveries and ongoing challenges, highlighting the need for continued research to fully elucidate the roles and regulation of protein phosphorylation.
Collapse
Affiliation(s)
- Thibault Houles
- Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, Quebec, Canada; Institute of Molecular Genetics of Montpellier (IGMM), Université de Montpellier, CNRS, Montpellier, France.
| | - Sang-Oh Yoon
- Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Philippe P Roux
- Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, Quebec, Canada; Department of Pathology and Cell Biology, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada.
| |
Collapse
|
|
6
|
Manzia TM, Antonelli B, Carraro A, Conte G, Guglielmo N, Lauterio A, Mameli L, Cillo U, De Carlis L, Del Gaudio M, De Simone P, Fagiuoli S, Lupo F, Tisone G, Volpes R. Immunosuppression in adult liver transplant recipients: a 2024 update from the Italian Liver Transplant Working Group. Hepatol Int 2024; 18:1416-1430. [PMID: 39009897 PMCID: PMC11461624 DOI: 10.1007/s12072-024-10703-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Accepted: 05/29/2024] [Indexed: 07/17/2024]
Abstract
PURPOSE Advances in surgical procedures and immunosuppressive therapies have considerably improved the outcomes of patients who have undergone liver transplantation in the past few decades. In 2020, the Italian Liver Transplant Working Group published practice-oriented algorithms for immunosuppressive therapy (IT) in adult liver transplant (LT) recipients. Due to the rapidly evolving LT field, regular updates to the recommendations are required. This review presents a consensus- and evidence-based update of the 2020 recommendations. METHODS The Italian Liver Transplant Working Group set out to address new IT issues, which were discussed based on supporting literature and the specialists' personal experiences. The panel deliberated on and graded each statement before consensus was reached. RESULTS A series of consensus statements were formulated and finalized on: (i) oncologic indications for LT; (ii) management of chronic LT rejection; (iii) combined liver-kidney transplantation; (iv) immunosuppression for transplantation with an organ donated after circulatory death; (v) transplantation in the presence of frailty and sarcopenia; and (vi) ABO blood group incompatibility between donor and recipient. Algorithms were updated in the following LT groups: standard patients, critical patients, oncology patients, patients with specific etiology, and patients at high immunologic risk. A steroid-free approach was generally recommended, except for patients with autoimmune liver disease and those at high immunologic risk. CONCLUSION The updated consensus- and evidence-based 2024 recommendations for immunosuppression regimens in adult patients with ABO-compatible LT address a range of clinical variables that should be considered to optimize the choice of the immunosuppression treatment in clinical practice in Italy.
Collapse
Affiliation(s)
| | - Barbara Antonelli
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Amedeo Carraro
- Liver Transplant Unit, University Hospital Trust of Verona, Verona, Italy
| | - Grazia Conte
- Clinica di Chirurgia Epatobiliare, Pancreatica e dei Trapianti, Azienda Ospedaliera Universitaria delle Marche, Ancona, Italy
| | - Nicola Guglielmo
- General Surgery and Liver Transplantation Unit, Azienda Ospedaliera San Camillo-Forlanini, Rome, Italy
| | - Andrea Lauterio
- ASST Grande Ospedale Metropolitano Niguarda, University of Milano-Bicocca, Milan, Italy
| | | | - Umberto Cillo
- Hepatobiliary and Liver Transplant Unit, University Hospital of Padua, Padua, Italy
| | - Luciano De Carlis
- Department of General Surgery and Transplantation, Niguarda Hospital, Milan, Italy
- School of Medicine, University of Milano-Bicocca, Milan, Italy
| | - Massimo Del Gaudio
- Department of General Surgery and Transplantation, Policlinico S. Orsola-Malpighi, Bologna, Italy
| | - Paolo De Simone
- Hepatobiliary Surgery and Liver Transplantation Unit, University of Pisa Medical School Hospital, Pisa, Italy
| | - Stefano Fagiuoli
- Gastroenterology, Department of Medicine, University of Milano-Bicocca and Gastroenterology Hepatology and Transplantation, Papa Giovanni XXIII Hospital, Piazza OMS, 124127, Bergamo, Italy.
| | - Francesco Lupo
- Department of General Surgery, Azienda Ospedaliera Città Della Salute e Della Scienza, Turin, Italy
| | | | - Riccardo Volpes
- Mediterranean Institute for Transplantation and Advanced Specialized Therapies (ISMETT/IRCCS), Palermo, Italy
- Fondazione Istituto G. Giglio di Cefalù, Palermo, Italy
| |
Collapse
|
|
7
|
Han A, Jo AJ, Kwon H, Kim YH, Lee J, Huh KH, Lee KW, Park JB, Jang E, Park SC, Lee J, Lee J, Kim Y, Soliman M, Min S. Optimum tacrolimus trough levels for enhanced graft survival and safety in kidney transplantation: a retrospective multicenter real-world evidence study. Int J Surg 2024; 110:6711-6722. [PMID: 38884261 PMCID: PMC11486932 DOI: 10.1097/js9.0000000000001800] [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: 04/09/2024] [Accepted: 06/03/2024] [Indexed: 06/18/2024]
Abstract
BACKGROUND The current study aimed to determine the optimal tacrolimus trough levels for balancing graft survival and patient safety following kidney transplantation. MATERIALS AND METHODS We conducted a retrospective cohort study involving 11 868 kidney transplant recipients from five medical centers. The association between tacrolimus exposures (periodic mean trough level, coefficient of variability, time in therapeutic range) and composite allograft outcome (de novo donor-specific antibody, biopsy-proven rejection, kidney dysfunction, and graft failure), as well as safety outcomes (severe infection, cardiovascular events, malignancy, and mortality) were assessed. Data were sourced from Clinical Data Warehouses and analyzed using advanced statistical methods, including Cox marginal structural models with inverse probability treatment weighting. RESULTS Tacrolimus levels of 5.0-7.9 ng/ml and 5.0-6.9 ng/ml during the 2-12 month and 12-72 month post-transplantation periods, respectively, were associated with reduced risks of composite allograft outcomes. During the first post-transplant year, the adjusted hazard ratios (aHR) for composite allograft outcomes were 0.69 (95% CI 0.55-0.85, P <0.001) for 5.0-5.9 ng/ml; 0.81 (95% CI 0.67-0.98, P =0.033) for 6.0-6.9 ng/ml; and 0.73 (95% CI 0.60-0.89, P =0.002) for 7.0-7.9 ng/ml (compared to levels ≥8.0 ng/ml). For the 6-year composite outcomes, aHRs were 0.68 (95% CI 0.53-0.87, P =0.002) for 5.0-5.9 ng/ml and 0.65 (95% CI 0.50-0.85, P =0.001) for 6.0-6.9 ng/ml. These optimal ranges showed reduced rates of severe infection (6 years), malignancy (6 years), and mortality (1 year). CONCLUSION This multicenter study provides robust evidence for optimal tacrolimus trough levels during the periods 2-12 and 12-72 months following kidney transplantation.
Collapse
Affiliation(s)
- Ahram Han
- Division of Transplantation and Vascular Surgery, Department of Surgery, Seoul National University Hospital, Seoul
| | - Ae Jeong Jo
- Department of Information Statistics, Andong National University, Andong
| | - Hyunwook Kwon
- Department of Kidney and Pancreases Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul
| | - Young Hoon Kim
- Department of Kidney and Pancreases Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul
| | - Juhan Lee
- Department of Surgery, Shinchon Severance Hospital, Yonsei University College of Medicine, Seoul
| | - Kyu Ha Huh
- Department of Surgery, Shinchon Severance Hospital, Yonsei University College of Medicine, Seoul
| | - Kyo Won Lee
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul
| | - Jae Berm Park
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul
| | - Eunju Jang
- Division of Vascular and Transplant Surgery, Department of Surgery, College of Medicine, The Catholic University of Korea, Seoul
| | - Sun Cheol Park
- Division of Vascular and Transplant Surgery, Department of Surgery, College of Medicine, The Catholic University of Korea, Seoul
| | - Joongyub Lee
- Department of Preventive Medicine, Seoul National University College of Medicine, Seoul
| | - Jeongyun Lee
- Medical Affairs Department, Astellas Pharma Korea, Seoul
| | - Younghye Kim
- Medical Affairs Department, Astellas Pharma Korea, Seoul
| | - Mohamed Soliman
- Medical Affairs Department, Astellas Pharma Singapore Pte Ltd., Singapore
| | - Sangil Min
- Division of Transplantation and Vascular Surgery, Department of Surgery, Seoul National University Hospital, Seoul
| |
Collapse
|
|
8
|
Shang S, Li W, Zhou F, Zhao Y, Yu M, Tong L, Xin H, Yu A. Cyclosporine-A induced cytotoxicity within HepG2 cells by inhibiting PXR mediated CYP3A4/CYP3A5/MRP2 pathway. Drug Chem Toxicol 2024; 47:739-747. [PMID: 38166548 DOI: 10.1080/01480545.2023.2276084] [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: 05/06/2023] [Revised: 09/16/2023] [Accepted: 10/13/2023] [Indexed: 01/04/2024]
Abstract
Cyclosporine-A (CsA) is currently used to treat immune rejection after organ transplantation as a commonly used immunosuppressant. Liver injury is one of the most common adverse effects of CsA, whose precise mechanism has not been fully elucidated. Pregnane X receptor (PXR) plays a critical role in mediating drug-induced liver injury as a key regulator of drug and xenobiotic clearance. As a nuclear receptor, PXR transcriptionally upregulates the expression of drug-metabolizing enzymes and drug transporters, including cytochrome P4503A (CPY3A) and multidrug resistance-associated protein 2 (MRP2). Our study established CsA-induced cytotoxic hepatocytes in an in vitro model, demonstrating that CsA dose-dependently increased the aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) level secreted in the HepG2 cell supernatant, as well as viability and oxidative stress of HepG2 cells. CsA also dose-dependently decreased the PXR, CYP3A4, CPY3A5, and MRP2 levels of HepG2 cells. Mechanistically, altering the expression of PXR, CYP3A4, CYP3A5, and MRP2 affected the impact of CsA on AST and LDH levels. Moreover, altering the expression of PXR also changed the level of CYP3A4, CPY3A5, and MRP2 of HepG2 cells treated by CsA. Our presented findings provide experimental evidence that CsA-induced liver injury is PXR tightly related. We suggest that PXR represents an attractive target for therapy of liver injury due to its central role in the regulation of the metabolizing enzymes CYP3A and MRP2-mediated bile acid transport and detoxification.
Collapse
Affiliation(s)
- Shenglan Shang
- Department of Clinical Pharmacy, General Hospital of Central Theater Command, Wuhan, Hubei Province, PR China
| | - Weiliang Li
- Department of Clinical Pharmacy, General Hospital of Central Theater Command, Wuhan, Hubei Province, PR China
| | - Fan Zhou
- Department of Clinical Pharmacy, General Hospital of Central Theater Command, Wuhan, Hubei Province, PR China
| | - Yan Zhao
- Department of Clinical Pharmacy, General Hospital of Central Theater Command, Wuhan, Hubei Province, PR China
| | - Mengchen Yu
- Department of Clinical Pharmacy, General Hospital of Central Theater Command, Wuhan, Hubei Province, PR China
| | - Ling Tong
- Department of Clinical Pharmacy, General Hospital of Central Theater Command, Wuhan, Hubei Province, PR China
| | - Huawen Xin
- Department of Clinical Pharmacy, General Hospital of Central Theater Command, Wuhan, Hubei Province, PR China
| | - Airong Yu
- Department of Clinical Pharmacy, General Hospital of Central Theater Command, Wuhan, Hubei Province, PR China
| |
Collapse
|
|
9
|
Choi JW, Shin J, Zhou Z, Song HJ, Bae GS, Kim MS, Park SJ. Myricetin ameliorates the severity of pancreatitis in mice by regulating cathepsin B activity and inflammatory cytokine production. Int Immunopharmacol 2024; 136:112284. [PMID: 38823179 DOI: 10.1016/j.intimp.2024.112284] [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: 04/01/2024] [Revised: 05/05/2024] [Accepted: 05/14/2024] [Indexed: 06/03/2024]
Abstract
Cathepsin B (CTSB) and inflammatory cytokines are critical in initiating and developing pancreatitis. Calcineurin, a central calcium (Ca2+)-responsive signaling molecule, mediates acinar cell death and inflammatory responses leading to pancreatitis. However, the detailed mechanisms for regulating CTSB activity and inflammatory cytokine production are unknown. Myricetin (MC) exhibits various biological activities, including anti-inflammatory effects. Here, we aimed to investigate MC effects on pancreatitis and the underlying mechanisms. Prophylactic and therapeutic MC treatment ameliorated the severity of cerulein-, L-arginine-, and PDL-induced acute pancreatitis (AP). The inhibition of CTSB activity by MC was mediated via decreased calcineurin activity and macrophage infiltration, not neutrophils infiltration, into the pancreas. Additionally, calcineurin activity inhibition by MC prevented the phosphorylation of Ca2+/CaM-dependent protein kinase kinase 2 (CaMKK2) during AP, resulting in the inhibition of CaMKIV phosphorylation and adenosine monophosphate-activated protein kinase (AMPK) dephosphorylation. Furthermore, MC reduced nuclear factor-κB activation by modulating the calcineurin-CaMKIV-IKKα/β-Iκ-Bα and calcineurin-AMPK-sirtuin1 axes, resulting in reduced production of tumor necrosis factor-α, interleukin (IL)-1β, and IL-6. Our results showed that MC alleviated AP severity by inhibiting acinar cell death and inflammatory responses, suggesting that MC as a calcineurin and CaMKK2 signaling modulator may be a potential treatment for AP.
Collapse
Affiliation(s)
- Ji-Won Choi
- Department of Herbology, School of Korean Medicine, Wonkwang University, Iksan-daero 460, Iksan, Jeollabuk-do 54538, Republic of Korea; Hanbang Cardio-Renal Syndrome Research Center, School of Korean Medicine, Wonkwang University, Iksan-daero 460, Iksan, Jeollabuk-do 54538, Republic of Korea
| | - Joonyeon Shin
- Department of Herbology, School of Korean Medicine, Wonkwang University, Iksan-daero 460, Iksan, Jeollabuk-do 54538, Republic of Korea; Hanbang Cardio-Renal Syndrome Research Center, School of Korean Medicine, Wonkwang University, Iksan-daero 460, Iksan, Jeollabuk-do 54538, Republic of Korea
| | - Ziqi Zhou
- Department of Herbology, School of Korean Medicine, Wonkwang University, Iksan-daero 460, Iksan, Jeollabuk-do 54538, Republic of Korea; Research Center of Traditional Korean Medicine, Wonkwang University, Iksan-daero 460, Iksan, Jeollabuk-do 54538, Republic of Korea
| | - Ho-Joon Song
- Department of Herbology, School of Korean Medicine, Wonkwang University, Iksan-daero 460, Iksan, Jeollabuk-do 54538, Republic of Korea
| | - Gi-Sang Bae
- Hanbang Cardio-Renal Syndrome Research Center, School of Korean Medicine, Wonkwang University, Iksan-daero 460, Iksan, Jeollabuk-do 54538, Republic of Korea; Department of Pharmacology, School of Korean Medicine, Wonkwang University, Iksan-daero 460, Iksan, Jeollabuk-do 54538, Republic of Korea; Research Center of Traditional Korean Medicine, Wonkwang University, Iksan-daero 460, Iksan, Jeollabuk-do 54538, Republic of Korea
| | - Min Seuk Kim
- Department of Oral Physiology, Institute of Biomaterial-Implant, School of Dentistry, Wonkwang University, Iksan, Jeonbuk 54538, Republic of Korea
| | - Sung-Joo Park
- Department of Herbology, School of Korean Medicine, Wonkwang University, Iksan-daero 460, Iksan, Jeollabuk-do 54538, Republic of Korea; Hanbang Cardio-Renal Syndrome Research Center, School of Korean Medicine, Wonkwang University, Iksan-daero 460, Iksan, Jeollabuk-do 54538, Republic of Korea; Research Center of Traditional Korean Medicine, Wonkwang University, Iksan-daero 460, Iksan, Jeollabuk-do 54538, Republic of Korea.
| |
Collapse
|
|
10
|
Maddur H, Wilson N, Patil P, Asrani S. Rejection in Liver Transplantation Recipients. J Clin Exp Hepatol 2024; 14:101363. [PMID: 38495462 PMCID: PMC10943490 DOI: 10.1016/j.jceh.2024.101363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 02/09/2024] [Indexed: 03/19/2024] Open
Abstract
Rejection following liver transplantation continues to impact transplant recipients although rates have decreased over time with advances in immunosuppression management. The diagnosis of rejection remains challenging with liver biopsy remaining the reference standard for diagnosis. Proper classification of rejection type and severity is imperative as this guides management and ultimately graft preservation. Future areas of promise include non-invasive testing for detection of rejection to reduce the morbidity associated with invasive testing and further advances in immunosuppression management to reduce toxicities associated with immunosuppression while minimizing rejection related morbidity.
Collapse
|
|
11
|
Geissbühler Y, Johnson JC, Gharbi H, Aubrun E, Kuessner D, Smolskis JM, Barcelos G, Prieto L. Treatment Switches, Patterns, and Outcomes in Adult and Pediatric Patients Undergoing Kidney Transplantation Between 2000 and 2019: A Retrospective United States Claims Database Study. Transplant Proc 2024; 56:1290-1299. [PMID: 39068098 DOI: 10.1016/j.transproceed.2024.05.040] [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: 01/16/2024] [Accepted: 05/24/2024] [Indexed: 07/30/2024]
Abstract
BACKGROUND Immunosuppressive regimens are imperative for improving patient and graft survival following kidney transplantation in patients with kidney failure. However, real-world evidence regarding treatments and outcomes in these patients is scarce. We sought to describe the treatment switches (assessed by line of treatment [LOT]), patterns, and outcomes in patients who underwent kidney transplantation in the United States. METHODS This retrospective cohort study used claims data from the Optum Research Database in the United States. Adult and pediatric patients undergoing a kidney transplantation between January 1, 2000, and June 30, 2019, who had ≥1 year of baseline and follow-up visits and continuous enrollment in the Optum Research Database, were included. RESULTS Data from 7159 patients (6833, adult; 326, pediatric) were included. The mean age for adult and pediatric patients was 51.4 ± 12.8 years and 10.4 ± 5.1 years, respectively. The mean number of LOTs in patients with ≥1 LOT (n = 7004) was 4.1 ± 2.6 LOTs. Tacrolimus, antiproliferative agents, and prednisone were the most frequently prescribed immunosuppressants. No strong correlations were identified between switching from LOT1 to LOT2 and potential predictors of treatment switches. The proportion of patients who did not experience graft loss gradually decreased between month 3 and month 120 (72%-36%), driven by return to dialysis (66%-18%). A slower decrease was observed for graft rejection (98%-84%), retransplantation (98%-93%), and graft removal (98%-92%). CONCLUSIONS We described treatment switches, patterns, and outcomes in patients who underwent kidney transplantation in the United States. Future analytical studies are needed to test hypotheses derived from these observations.
Collapse
Affiliation(s)
| | | | | | | | | | | | - Giovanna Barcelos
- Novartis Pharma AG, Basel, Switzerland; Pfizer AG, Zurich, Switzerland
| | | |
Collapse
|
|
12
|
Provenzano M, Hu L, Tringali E, Senatore M, Talarico R, Di Dio M, Ruotolo C, La Manna G, Garofalo C, Zaza G. Improving Kidney Disease Care: One Giant Leap for Nephrology. Biomedicines 2024; 12:828. [PMID: 38672183 PMCID: PMC11048002 DOI: 10.3390/biomedicines12040828] [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: 02/18/2024] [Revised: 03/24/2024] [Accepted: 03/27/2024] [Indexed: 04/28/2024] Open
Abstract
Nephrology is an ever-evolving field of medicine. The importance of such a discipline is related to the high clinical impact of kidney disease. In fact, abnormalities of kidney function and/or structure are common in the general population, reaching an overall prevalence of about 10%. More importantly, the onset of kidney damage is related to a strikingly high risk of cardiovascular events, mortality, and progression to kidney failure which, in turn, compromises quality and duration of life. Attempts to comprehend the pathogenesis and molecular mechanisms involved in kidney disease occurrence have prompted the development and implementation of novel drugs in clinical practice with the aim of treating the 'specific cause' of kidney disease (including chronic kidney disease, glomerular disease, and genetic kidney disorders) and the main immunological complications following kidney transplantation. Herein, we provide an overview of the principal emerging drug classes with proved efficacy in the context of the aforementioned clinical conditions. This can represent a simplified guide for clinical nephrologists to remind them of the vast and heterogeneous armamentarium of drugs that should be used in the present and the future to improve the management of patients suffering from kidney disease.
Collapse
Affiliation(s)
- Michele Provenzano
- Department of Pharmacy Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy; (M.S.); (R.T.)
| | - Lilio Hu
- Nephrology, Dialysis and Kidney Transplant Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (L.H.); (E.T.); (G.L.M.)
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy
| | - Edoardo Tringali
- Nephrology, Dialysis and Kidney Transplant Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (L.H.); (E.T.); (G.L.M.)
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy
| | - Massimo Senatore
- Department of Pharmacy Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy; (M.S.); (R.T.)
| | - Roberta Talarico
- Department of Pharmacy Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy; (M.S.); (R.T.)
| | - Michele Di Dio
- Division of Urology, Department of Surgery, SS Annunziata Hospital, 87100 Cosenza, Italy;
| | - Chiara Ruotolo
- Unit of Nephrology, Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy; (C.R.); (C.G.)
| | - Gaetano La Manna
- Nephrology, Dialysis and Kidney Transplant Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (L.H.); (E.T.); (G.L.M.)
- Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy
| | - Carlo Garofalo
- Unit of Nephrology, Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy; (C.R.); (C.G.)
| | - Gianluigi Zaza
- Department of Pharmacy Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy; (M.S.); (R.T.)
| |
Collapse
|
|
13
|
Jiang Y, Tao M, Chen J, Luo L, You Q, Wu H, Zhang N. Calcineurin inhibitors in the treatment of systemic lupus erythematosus during pregnancy: A narrative review with emphasis on efficacy and safety. Eur J Obstet Gynecol Reprod Biol 2024; 294:148-155. [PMID: 38245953 DOI: 10.1016/j.ejogrb.2023.12.039] [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: 10/22/2023] [Revised: 11/21/2023] [Accepted: 12/31/2023] [Indexed: 01/23/2024]
Abstract
Systemic lupus erythematosus (SLE) predominantly affects child-bearing women, leading to an elevated risk of maternal and fetal complications and adverse pregnancy outcomes. Since some medications can cross the placental barrier that persist a threat to both mother and fetus, the risk-benefit ratio of SLE medications should be taken into consideration during pregnancy. Calcineurin inhibitor (CNI), mainly including cyclosporin A, tacrolimus, and voclosporin, is a category of immunosuppressive agents that inhibit calcium/calmodulin-dependent phosphatase calcineurin to block T cell activation. Based on the current clinical evidence, CNI is an alternative in pregnant SLE patients with persistent disease activity (especially lupus nephritis patients) and non-responders to azathioprine. However, there is no comprehensive review that summarizes the efficacy and safety profile of CNI for SLE management during pregnancy. This review presents a summary on the utilization of CNI for SLE management during pregnancy, including the mechanism of action, gestational amelioration of lupus flare, and the balance of maternal benefit-fetal risk, which may provide more references for the management of SLE pregnancies.
Collapse
Affiliation(s)
- Yi Jiang
- Department of Rheumatology and Immunology, The First Hospital Affiliated to Army Medical University, Chongqing 400038, China
| | - Min Tao
- Department of Pediatrics, The First Hospital Affiliated to Army Medical University, Chongqing 400038, China
| | - Jingjing Chen
- Department of Rheumatology and Immunology, The First Hospital Affiliated to Army Medical University, Chongqing 400038, China
| | - Lihua Luo
- Department of Rheumatology and Immunology, The First Hospital Affiliated to Army Medical University, Chongqing 400038, China
| | - Qingxia You
- Department of Rheumatology and Immunology, The First Hospital Affiliated to Army Medical University, Chongqing 400038, China
| | - Hong Wu
- Department of Rheumatology and Immunology, The First Hospital Affiliated to Army Medical University, Chongqing 400038, China
| | - Nian Zhang
- Department of Traditional Chinese Medicine, The Second Hospital Affiliated to Army Medical University, Chongqing 400037, China.
| |
Collapse
|
|
14
|
Luft FC. Calcineurin inhibition, cardiovascular consequences, vascular resistance, and potential responses. Acta Physiol (Oxf) 2024; 240:e14084. [PMID: 38214031 DOI: 10.1111/apha.14084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 10/20/2023] [Accepted: 01/01/2024] [Indexed: 01/13/2024]
Abstract
AIM To place the consequences of calcineurin inhibition in a cardiovascular context. METHODS Literature review coupled with personal encounters. RESULTS Calcineurin is a calcium-binding and calmodulin-binding protein that is conserved across evolution from yeast to mammals. The enzyme functions as a calcium-dependent, calmodulin-stimulated protein phosphatase. Its role in regulating physiology has largely been elucidated by observing calcineurin inhibition. Calcineurin inhibition transformed organ transplantation from an experiment into a therapy and made much of general immunotherapy possible. The function of this phosphatase and how its inhibition leads to toxicity concern us to this date. Initial research from patients and animal models implicated a panoply of factors contributing to hypertension and vasculopathy. Subsequently, the role of calcineurin in regulating the effective fluid volume, sodium reabsorption, and potassium and hydrogen ion excretion was elucidated by investigating calcineurin inhibition. Understanding the regulatory effects of calcineurin on endothelial and vascular smooth muscle cell function has also made substantial progress. However, precisely how the increase in systemic vascular resistance arises requires further mechanistic research. CONCLUSION Calcineurin inhibition continues to save lives; however, options to counteract the negative effects of calcineurin inhibition should be vigorously pursued.
Collapse
Affiliation(s)
- Friedrich C Luft
- Experimental and Clinical Research Center, a cooperation between the Max-Delbrück Center for Molecular Medicine and the Charité Medical Faculty, Berlin, Germany
| |
Collapse
|
|
15
|
Born A, Bocchi F, Kuhn C, Amstutz U, Baumgartner MR, Sidler D. Tacrolimus monitoring in hair samples of kidney transplant recipients. Front Med (Lausanne) 2023; 10:1307505. [PMID: 38111700 PMCID: PMC10726046 DOI: 10.3389/fmed.2023.1307505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Accepted: 11/15/2023] [Indexed: 12/20/2023] Open
Abstract
Background Calcineurin inhibitors, including tacrolimus, remain a cornerstone of immunosuppressive therapy after kidney transplantation. However, the therapeutic window is narrow, and nephrotoxic side effects occur with overdose, while the risk of alloimmunization and graft rejection increases with underdose. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) allows quantification of tacrolimus in biological samples from patients. This study investigates the feasibility of quantifying tacrolimus in scalp hair from kidney transplant (KT) recipients and correlates hair tacrolimus concentrations with tacrolimus dosage and blood trough levels. The aim was to provide proof-of-principle for hair tacrolimus drug monitoring in KT recipients. Method Single-center prospective study between September 9, 2021 and December 4, 2021, including KT recipients under tacrolimus. Minors, patients with active skin or hair diseases, and patients with scalp hair shorter than 4 cm were excluded from participation. Scalp hair was collected from the posterior vertex of patients, cut into segments, and analyzed for tacrolimus by LC-MS/MS. Patients filled out a questionnaire on hair treatments and washing habits. In parallel, tacrolimus trough levels were measured in whole blood and correlated with hair tacrolimus concentrations. Results In total, 39 consenting KT recipients were included, and hair samples were collected at 53 visits. Tacrolimus was detected in 98% of hair samples from patients exposed to the drug. Tacrolimus hair levels and whole blood trough levels were correlated with a beta coefficient of 0.42 (95% CI: -0.22-1.1, p = n.s.). Age and dark hair affected hair tacrolimus measurements, while different tacrolimus formulations (immediate release vs. extended release), hair washes, and permanent coloring did not. Longitudinal measurements in a subgroup of patients indicate that long-term measurement of hair tacrolimus levels is feasible. Conclusion Measuring tacrolimus in hair is a potentially reliable method to monitor drug exposure in KT patients. Rapid wash-in effects and consistent concentrations over time indicate that tacrolimus is incorporated into the hair matrix, allowing temporal resolution in the analysis of recent exposure and exposure history. This method provides a simple and low-risk alternative to regular blood sampling, sparing patients from frequent hospital visits through the self-collection of hair samples.
Collapse
Affiliation(s)
- Alexander Born
- Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Federica Bocchi
- Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Christian Kuhn
- Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Ursula Amstutz
- Department of Clinical Chemistry, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | | | - Daniel Sidler
- Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| |
Collapse
|
|
16
|
Antala S, DiNorcia J, Bucuvalas J. Balancing immunosuppression in pediatric liver transplantation: Playing the long game. Pediatr Transplant 2023; 27:e14575. [PMID: 37439035 DOI: 10.1111/petr.14575] [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: 05/08/2023] [Accepted: 07/03/2023] [Indexed: 07/14/2023]
Abstract
The overarching goal in the care of pediatric liver transplant recipients is to optimize allograft and patient health. Balancing immunosuppression to maintain allograft health while avoiding medication side effects is essential for long-term survival and optimal quality of life in pediatric liver transplant recipients. Utilizing precision medicine to personalize immunosuppression, which includes minimization and withdrawal, is core to this effort. The unique anatomy and physiology of the liver make it more tolerant to immune-mediated injury and a more favorable organ for immunosuppression minimization and withdrawal. However, several challenges exist. Standard biochemical values and histologic features may not reliably predict allograft health after a reduction in immunosuppression. Additionally, biochemical values alone do not reliably identify which patients can successfully develop operational tolerance, as there may be occult allograft injury despite normal liver enzymes. Finally, the durability of tolerance after successful reduction in immunosuppression remains uncertain over time. Innovative tools show promise in circumventing these challenges, but more research is needed to determine actual clinical utility. While immunosuppression-free transplant may not be a current reality for most pediatric liver transplant recipients, strategies to safely minimize immunosuppression without compromising allograft health are within reach. Each liver allograft and recipient pair requires a different degree of immune modulation, and through a structured process of minimization and withdrawal, immunosuppression can indeed be tailored in a precise, personalized way to optimize outcomes. This review focuses on the progress that has been made to individualize immunosuppression in pediatric liver transplantation to ensure optimal allograft and recipient health.
Collapse
Affiliation(s)
- Swati Antala
- Department of Pediatrics, Icahn School of Medicine, Kravis Children's Hospital at Mount Sinai, New York City, New York, USA
| | - Joseph DiNorcia
- Recanati-Miller Transplantation Institute, Mount Sinai Hospital, New York City, New York, USA
| | - John Bucuvalas
- Department of Pediatrics, Icahn School of Medicine, Kravis Children's Hospital at Mount Sinai, New York City, New York, USA
| |
Collapse
|
|
17
|
Cavalcante MB, Tavares ACM, Rocha CA, de Souza GF, Lima EM, Simões JML, de Souza LC, Martins MYM, de Araújo NO, Barini R. Calcineurin inhibitors in the management of recurrent miscarriage and recurrent implantation failure: Systematic review and meta-analysis. J Reprod Immunol 2023; 160:104157. [PMID: 37813069 DOI: 10.1016/j.jri.2023.104157] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 09/26/2023] [Accepted: 09/27/2023] [Indexed: 10/11/2023]
Abstract
Recurrent miscarriage (RM) affects up to 2.5% of couples of reproductive age. Up to 10% of couples using assisted reproductive technology experience recurrent implantation failure (RIF). Immunosuppressive drugs, such as calcineurin inhibitors (CNIs), has been proposed for RM and RIF management. This systematic review and meta-analysis (SRMA) aimed to evaluate the efficacy and safety of CNIs in RM and RIF treatment. We searched in the three databases. Review Manager 5.4.1 was used for statistical analysis. This review included 8 studies involving 1042 women (485 women in the CNIs group and 557 women in the control group). CNI treatment (cyclosporine [CsA] and tacrolimus [TAC]) increases live birth rate (LBR, odds ratio [OR]: 2.52; 95% confidence interval [CI]: 1.93-3.28, p < 0.00001) and clinical pregnancy rate (OR: 2.25; 95% CI: 1.54-4.40, p < 0.0001) and decreases miscarriage rate (OR: 0.45 95% CI: 0.32-0.63, p < 0.00001) when compared to the control. Side effects and obstetric and neonatal complications was similar in both groups. In conclusion, CNIs increased LBR in women with RM and RIF but there is a moderate risk of bias. Subgroup analysis revealed that CNIs improved LBR in women with RM with a low risk of bias. However, in women with RIF, with moderate to high risk of bias. The use of CsA and TAC, in low doses and for a short period, for managing reproductive failures in women seems to be safe, not causing serious side effects nor increasing the risk of obstetric and neonatal complications.
Collapse
Affiliation(s)
- Marcelo Borges Cavalcante
- Postgraduate Program in Medical Sciences, Universidade de Fortaleza (UNIFOR), Fortaleza, CE 60.811-905, Brazil; CONCEPTUS - Reproductive Medicine, Fortaleza, CE 60.170-240, Brazil; Medical Course, Universidade de Fortaleza (UNIFOR), Fortaleza, CE 60.811-905, Brazil.
| | | | - Camila Alves Rocha
- Medical Course, Universidade de Fortaleza (UNIFOR), Fortaleza, CE 60.811-905, Brazil
| | | | - Eduarda Maia Lima
- Medical Course, Universidade de Fortaleza (UNIFOR), Fortaleza, CE 60.811-905, Brazil
| | | | - Larissa Cruz de Souza
- Medical Course, Universidade de Fortaleza (UNIFOR), Fortaleza, CE 60.811-905, Brazil
| | | | | | - Ricardo Barini
- Department of Obstetrics and Gynecology, Campinas University (UNICAMP), Campinas, SP 13.083-887, Brazil
| |
Collapse
|
|
18
|
Lassiter G, Otsuka R, Hirose T, Rosales I, Karadagi A, Tomosugi T, Dehnadi A, Lee H, Colvin RB, Baardsnes J, Moraitis A, Smith EE, Ali Z, Berhe P, Mulder A, Meibohm B, Daugherty B, Fogarty S, Pierson RN, Lederman S, Kawai T. TNX-1500, a crystallizable fragment-modified anti-CD154 antibody, prolongs nonhuman primate renal allograft survival. Am J Transplant 2023; 23:1171-1181. [PMID: 37019335 PMCID: PMC10527606 DOI: 10.1016/j.ajt.2023.03.022] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 03/23/2023] [Accepted: 03/24/2023] [Indexed: 04/05/2023]
Abstract
The blockade of the CD154-CD40 pathway with anti-CD154 monoclonal antibody has been a promising immunomodulatory approach to prevent allograft rejection. However, clinical trials of immunoglobulin G1 antibodies targeting this pathway revealed thrombogenic properties, which were subsequently shown to be mediated by crystallizable fragment (Fc)-gamma receptor IIa-dependent platelet activation. To prevent thromboembolic complications, an immunoglobulin G4 anti-CD154 monoclonal antibody, TNX-1500, which retains the fragment antigen binding region of ruplizumab (humanized 5c8, BG9588), was modified by protein engineering to decrease Fc binding to Fc-gamma receptor IIa while retaining certain other effector functions and pharmacokinetics comparable with natural antibodies. Here, we report that TNX-1500 treatment is not associated with platelet activation in vitro and consistently inhibits kidney allograft rejection in vivo without clinical or histologic evidence of prothrombotic phenomena. We conclude that TNX-1500 retains efficacy similar to that of 5c8 to prevent kidney allograft rejection while avoiding previously identified pathway-associated thromboembolic complications.
Collapse
Affiliation(s)
- Grace Lassiter
- Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Ryo Otsuka
- Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Takayuki Hirose
- Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Ivy Rosales
- Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Ahmad Karadagi
- Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Toshihide Tomosugi
- Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Abbas Dehnadi
- Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Hang Lee
- Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Robert B Colvin
- Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | | | - Anna Moraitis
- National Research Council, Montréal, Quebec H4P 2R2, Canada
| | - Emma E Smith
- National Research Council, Montréal, Quebec H4P 2R2, Canada
| | - Zahida Ali
- Charles River Laboratories, Skokie, Illinois, USA
| | - Phil Berhe
- Charles River Laboratories, Skokie, Illinois, USA
| | | | - Bernd Meibohm
- College of Pharmacy, University of Tennessee Health Science Center, Memphis, Tennesse, USA
| | | | | | - Richard N Pierson
- Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Seth Lederman
- Tonix Pharmaceuticals, Inc, Chatham, New Jersey, USA
| | - Tatsuo Kawai
- Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
| |
Collapse
|
|
19
|
Lim IV, Yurttaş NÖ, Ayer M, Poturoğlu Ş, Kınacı E, Özden İ. Entecavir-induced neutropenia in an adult living donor liver transplant recipient: Successful conversion to tenofovir alafenamide. Clin Case Rep 2023; 11:e7741. [PMID: 37575459 PMCID: PMC10421973 DOI: 10.1002/ccr3.7741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 07/18/2023] [Accepted: 07/19/2023] [Indexed: 08/15/2023] Open
Abstract
At 22 weeks post-transplantation for HBV-related cirrhosis, an adult woman developed neutropenia which was aggravated by COVID-19 (ANC 0.4 × 109/L). Covid resolution and all "conventional" modifications were ineffective. Success within 2 weeks was achieved by switching entecavir to tenofovir alafenamide. A step-by-step judicious approach to post-transplant neutropenia is vital.
Collapse
Affiliation(s)
- I. Vern Lim
- Department of General Surgery, Liver Transplantation & Hepatopancreatobiliary Surgery UnitBaşakşehir Çam & Sakura City HospitalIstanbulTurkey
| | - Nurgül Özgür Yurttaş
- Department of Internal Medicine, Division of HematologyBaşakşehir Çam & Sakura City HospitalIstanbulTurkey
| | - Mesut Ayer
- Department of Internal Medicine, Division of HematologyBaşakşehir Çam & Sakura City HospitalIstanbulTurkey
| | - Şule Poturoğlu
- Department of Internal Medicine, Division of GastroenterologyBaşakşehir Çam & Sakura City HospitalIstanbulTurkey
| | - Erdem Kınacı
- Department of General Surgery, Liver Transplantation & Hepatopancreatobiliary Surgery UnitBaşakşehir Çam & Sakura City HospitalIstanbulTurkey
| | - İlgin Özden
- Department of General Surgery, Liver Transplantation & Hepatopancreatobiliary Surgery UnitBaşakşehir Çam & Sakura City HospitalIstanbulTurkey
| |
Collapse
|
|
20
|
Hadpech S, Chaiyarit S, Thongboonkerd V. Calcineurin B inhibits calcium oxalate crystallization, growth and aggregation via its high calcium-affinity property. Comput Struct Biotechnol J 2023; 21:3854-3864. [PMID: 37593722 PMCID: PMC10427926 DOI: 10.1016/j.csbj.2023.07.038] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 07/30/2023] [Accepted: 07/30/2023] [Indexed: 08/19/2023] Open
Abstract
Calcineurin inhibitors (CNIs) are widely used in organ transplantation to suppress immunity and prevent allograft rejection. However, some transplant patients receiving CNIs have hypocitraturia, hyperoxaluria and kidney stone with unclear mechanism. We hypothesized that CNIs suppress activities of urinary calcineurin, which may serve as the stone inhibitor. This study aimed to investigate effects of calcineurin B (CNB) on calcium oxalate monohydrate (COM) stone formation. Sequence and structural analyses revealed that CNB contained four EF-hand (Ca2+-binding) domains, which are known to regulate Ca2+ homeostasis and likely to affect COM crystals. Various crystal assays revealed that CNB dramatically inhibited COM crystallization, crystal growth and crystal aggregation. At an equal amount, degrees of its inhibition against crystallization and crystal growth were slightly inferior to total urinary proteins (TUPs) from healthy subjects that are known to strongly inhibit COM stone formation. Surprisingly, its inhibitory effect against crystal aggregation was slightly superior to TUPs. While TUPs dramatically inhibited crystal-cell adhesion, CNB had no effect on this process. Ca2+-affinity assay revealed that CNB strongly bound Ca2+ at a comparable degree as of TUPs. These findings indicate that CNB serves as a novel inhibitor of COM crystallization, growth and aggregation via its high Ca2+-affinity property.
Collapse
Affiliation(s)
- Sudarat Hadpech
- Medical Proteomics Unit, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Sakdithep Chaiyarit
- Medical Proteomics Unit, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Visith Thongboonkerd
- Medical Proteomics Unit, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| |
Collapse
|
|
21
|
Kaplan A, Korenjak M, Brown RS. Post-liver transplantation patient experience. J Hepatol 2023; 78:1234-1244. [PMID: 37208108 DOI: 10.1016/j.jhep.2023.01.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 01/02/2023] [Accepted: 01/12/2023] [Indexed: 05/21/2023]
Abstract
Given improvements in post-transplant patient and graft survival, there is a growing need to focus on patient experience and health-related quality of life (HRQOL). Though liver transplantation can be life-saving, it can also be associated with significant morbidity and complications. Patient HRQOL improves after transplantation, but it may not improve to that of age-matched cohorts. Understanding patient experience and the factors that contribute to it, including physical and psychological health, immunosuppression and medication adherence, return to employment or school, financial burden, and expectations, helps when thinking creatively about potential interventions to improve HRQOL.
Collapse
Affiliation(s)
- Alyson Kaplan
- Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell School of Medicine, New York Presbyterian, New York, NY, USA
| | | | - Robert S Brown
- Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell School of Medicine, New York Presbyterian, New York, NY, USA.
| |
Collapse
|
|
22
|
Kaneko M, Jackson SW. Recent advances in immunotherapies for lupus nephritis. Pediatr Nephrol 2023; 38:1001-1012. [PMID: 35778517 PMCID: PMC10219838 DOI: 10.1007/s00467-022-05670-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 06/03/2022] [Accepted: 06/20/2022] [Indexed: 11/24/2022]
Abstract
Childhood-onset systemic lupus erythematosus (SLE) is characterized by increased rates of kidney involvement, termed lupus nephritis. Despite the significant morbidity and mortality associated with this disease, lupus nephritis trials have been plagued by repeated failures to meet clinical endpoints. However, improvements in trial design and the development of targeted approaches have begun to yield promising results, including two new FDA-approved lupus nephritis treatments since 2020. These include belimumab, a monoclonal antibody targeting the B cell survival cytokine BAFF (B cell activating factor), and voclosporin, a cyclosporin analog with improved pharmacokinetic characteristics. In this review, we will summarize the data supporting regulatory approval for these agents in lupus nephritis and highlight ongoing clinical trials targeting the diverse immunologic drivers of renal inflammation in SLE. While pediatric patients remain underrepresented in lupus clinical trials, given the increased severity of childhood-onset SLE and need for long-term protection from kidney damage, we anticipate the need for off-label use of these targeted therapies in the pediatric population. Future studies are needed to define optimal patient selection, drug combinations, and treatment duration in pediatric lupus nephritis.
Collapse
Affiliation(s)
- Machi Kaneko
- Division of Pediatric Nephrology, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA
| | - Shaun W Jackson
- Division of Pediatric Nephrology, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA.
- Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA, USA.
- Seattle Childrens Research Institute, 1900 Ninth Avenue, M/S JMB-6, WA, 98101, Seattle, USA.
| |
Collapse
|
|
23
|
Gaudji GR, Bida M, Conradie M, Damane BP, Bester MJ. Renal Papillary Necrosis (RPN) in an African Population: Disease Patterns, Relevant Pathways, and Management. Biomedicines 2022; 11:biomedicines11010093. [PMID: 36672600 PMCID: PMC9855351 DOI: 10.3390/biomedicines11010093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 12/02/2022] [Accepted: 12/26/2022] [Indexed: 12/31/2022] Open
Abstract
Renal papillary necrosis (RPN) is characterized by coagulative necrosis of the renal medullary pyramids and papillae. Multiple conditions and toxins are associated with RPN. Several RPN risk factors, or POSTCARDS, have been identified, with most patients presenting with RPN having at least two contributing risk factors. Currently, there is no specific test to diagnose and confirm RPN; however, several imaging tools can be used to diagnose the condition. RPN is currently underdiagnosed in African populations, often with fatal outcomes. In African clinical settings, there is a lack of consensus on how to define and describe RPN in terms of kidney anatomy, pathology, endourology, epidemiology, the identification of African-specific risk factors, the contribution of oxidative stress, and lastly an algorithm for managing the condition. Several risk factors are unique to African populations including population-specific genetic factors, iatrogenic factors, viral infections, antimicrobial therapy, schistosomiasis, substance abuse, and hypertension (GIVASSH). Oxidative stress is central to both GIVASSH and POSTCARDS-associated risk factors. In this review, we present information specific to African populations that can be used to establish an updated consensual definition and practical grading system for radiologists, urologists, nephrologists, nuclear physicians, and pathologists in African clinical settings.
Collapse
Affiliation(s)
- Guy Roger Gaudji
- Department of Urology, Steve Biko Academic Hospital, Faculty of Health Sciences, University of Pretoria, Pretoria 0007, South Africa
- Correspondence: (G.R.G.); (M.J.B.)
| | - Meshack Bida
- Department of Anatomical Pathology, National Health Laboratory Service (NHLS), Faculty of Health Sciences, University of Pretoria, Pretoria 0084, South Africa
| | - Marius Conradie
- Urology Practice, Netcare Waterfall City Hospital, Cnr Magwa Avenue and Mac Mac Road, Johannesburg 1682, South Africa
| | - Botle Precious Damane
- Department of Surgery, Steve Biko Academic Hospital, Faculty of Health Sciences, University of Pretoria, Pretoria 0007, South Africa
| | - Megan Jean Bester
- Department of Anatomy, Faculty of Health Sciences, University of Pretoria, Pretoria 0007, South Africa
- Correspondence: (G.R.G.); (M.J.B.)
| |
Collapse
|
|
24
|
Tharanon V, Putthipokin K, Sakthong P. Drug-related problems identified during pharmaceutical care interventions in an intensive care unit at a tertiary university hospital. SAGE Open Med 2022; 10:20503121221090881. [PMID: 35465635 PMCID: PMC9021480 DOI: 10.1177/20503121221090881] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 03/11/2022] [Indexed: 11/16/2022] Open
Abstract
Introduction Drug-related problems could potentially worsen the clinical outcomes in critically ill patients. Critically ill patients are generally considered more vulnerable to harm from drug-related problems due to frequent medication-related events and complicated clinical courses. However, drug-related problems identified by on-ward clinical pharmacists in medical intensive care units in Thailand are not well reported. This study reports clinically relevant data with the description of identified problems, common causes of drug-related problems, and pharmacists' interventions performed in real world, so that it may serve as an educational material for pharmacists who implement a pharmaceutical care and participate in medical intensive care units. Methods A retrospective descriptive study was conducted at a tertiary university hospital in Bangkok, Thailand, from January 2015 to December 2020. The drug-related problems were categorized according to Cipolle et al.'s classification. The severity of drug-related problems in this study was rated by modifying the definition of The National Coordinating Council for Medication Error Reporting and Prevention Taxonomy of Medication Error to report harm from drug-related problem-related patient outcomes. Results A total of 698 drug-related problems were detected in 374 critically ill patients. The prevalence of drug-related problems occurring in critically ill patients admitted to the medical intensive care unit was 73.9%. The most frequent drug-related problems were dosage too high (27.7%), ineffective drug (17.2%), need for additional drug therapy (15.3%), unnecessary drug therapy (14.6%), dosage too low (14.3%), adverse drug reaction (9.7%), and non-adherence (1.2%). The severity of drug-related problems in the medical intensive care unit was assessed as a drug-related problem with no harm (78.2%). Pharmacists' interventions were advised according to drug-related problem identification to provide personalized pharmacotherapy optimization in critically ill patients. Conclusion The most frequent drug-related problem identified during pharmaceutical care interventions in the medical intensive care unit at tertiary university hospital is dosage too high. The severity of drug-related problems is mostly determined as drug-related problems with no harm.
Collapse
Affiliation(s)
- Vichapat Tharanon
- Clinical Pharmacy Section, Pharmacy Division, Ramathibodi Hospital, Bangkok, Thailand
| | - Krongtong Putthipokin
- Clinical Pharmacy Section, Pharmacy Division, Ramathibodi Hospital, Bangkok, Thailand
| | - Phantipa Sakthong
- Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand
| |
Collapse
|
|
25
|
Wambach JA, Nogee LM, Cole FS. First Steps toward Personalized Therapies for ABCA3 Deficiency. Am J Respir Cell Mol Biol 2022; 66:349-350. [PMID: 35077664 PMCID: PMC8990116 DOI: 10.1165/rcmb.2021-0405ed] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Affiliation(s)
- Jennifer A Wambach
- Edward Mallinckrodt Department of Pediatric Washington University School of Medicine St. Louis, Missouri
| | - Lawrence M Nogee
- Department of Pediatrics Johns Hopkins University School of Medicine Baltimore, Maryland
| | - F Sessions Cole
- Edward Mallinckrodt Department of Pediatric Washington University School of Medicine St. Louis, Missouri
| |
Collapse
|
|
26
|
Zheng Z, Zhang H, Peng X, Zhang C, Xing C, Xu G, Fu P, Ni Z, Chen J, Xu Z, Zhao MH, Li S, Huang X, Miao L, Chen X, Liu B, He Y, Li J, Liu L, Kadeerbai H, Liu Z, Liu Z. Effect of Tacrolimus vs Intravenous Cyclophosphamide on Complete or Partial Response in Patients With Lupus Nephritis: A Randomized Clinical Trial. JAMA Netw Open 2022; 5:e224492. [PMID: 35353167 PMCID: PMC8969066 DOI: 10.1001/jamanetworkopen.2022.4492] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
IMPORTANCE Lupus nephritis (LN) is typically treated with intravenous cyclophosphamide (IVCY), which is associated with serious adverse effects. Tacrolimus may be an alternative for initial treatment of LN; however, large-scale, randomized clinical studies of tacrolimus are lacking. OBJECTIVE To assess efficacy and safety of tacrolimus vs IVCY as an initial therapy for LN in China. DESIGN, SETTING, AND PARTICIPANTS This randomized (1:1), open-label, parallel-controlled, phase 3, noninferiority clinical trial recruited patients aged 18 to 60 years with systemic lupus erythematosus and LN class III, IV, V, III+V, or IV+V primarily from outpatient settings at 35 centers in China. Inclusion criteria included body mass index of 18.5 or greater to less than 27, 24-hour urine protein of 1.5 g or greater, and serum creatinine of less than 260 μmol/L. Of 505 patients screened, 191 failed screening (163 ineligible, 25 withdrawn consent, and 3 other reasons). Overall, 314 were randomized. The first patient was enrolled March 10, 2015, and the study finished September 13, 2018. The follow-up period was 24 weeks. Data were analyzed from December 2019 to March 2020. INTERVENTIONS Oral tacrolimus (target trough level, 4-10 ng/mL) or IVCY for 24 weeks plus prednisone. MAIN OUTCOMES AND MEASURES Complete or partial response rate at week 24 (prespecified). RESULTS A total of 314 patients were randomized (158 [50.3%] to tacrolimus and 156 [49.7%] to IVCY). Overall, 299 patients (95.2%) were treated (tacrolimus group, 157 [52.5%]; IVCY group, 142 [47.5%]). Baseline demographic and clinical characteristics were generally similar between groups (mean [SD] age, 34.2 [9.5] years; 262 [87.6%] female). Tacrolimus was found to be noninferior to IVCY for LN response at week 24. There was a complete or partial response rate of 83.0% (117 of 141 patients) in the tacrolimus group and 75.0% (93 of 124 patients) in the IVCY group (difference, 7.1%; 2-sided 95% CI, -2.7% to 16.9%; lower limit of 95% CI greater than -15%). At week 24, least-square mean change in Systemic Lupus Erythematosus Disease Activity Index score was -8.6 with tacrolimus and -6.4 with IVCY (difference, -2.2; 95% CI, -3.1 to -1.3). Changes in other immune parameters and kidney function were generally similar between groups. Serious treatment-emergent adverse events (TEAEs) were reported in 29 patients in the tacrolimus group (18.5%) and 35 patients in the IVCY group (24.6%). Most common serious study drug-related TEAEs were infections (14 [8.9%] and 23 [16.2%], respectively). Seven patients in each group withdrew due to AEs. CONCLUSIONS AND RELEVANCE In this study, oral tacrolimus appeared noninferior to IVCY for initial therapy of active LN, with a more favorable safety profile than IVCY. Tacrolimus may be an alternative to IVCY as initial therapy for LN. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02457221.
Collapse
Affiliation(s)
- Zhaohui Zheng
- Department of Rheumatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Haitao Zhang
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu, China
| | - Xiaomei Peng
- Department of Nephrology, The People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Chun Zhang
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Changying Xing
- Department of Nephrology, The First Affiliated Hospital of Nanjing Medical University, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Gang Xu
- Department of Nephrology, Tongji Hospital affiliated with Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Ping Fu
- Renal Division, Department of Medicine, West China Hospital of Sichuan University, Kidney Research Institute, Chengdu, Sichuan, China
| | - Zhaohui Ni
- Department of Nephrology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Jianghua Chen
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Zhonggao Xu
- Department of Nephrology, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Ming-hui Zhao
- Renal Division, Department of Medicine, Peking University First Hospital, Institute of Nephrology, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment, Ministry of Education of China, and Peking-Tsinghua Center for Life Sciences, Beijing, China
| | - Shaomei Li
- Department of Nephrology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Xiangyang Huang
- Department of Nephrology, Liuzhou Worker’s Hospital, Liuzhou, Guangxi, China
| | - Lining Miao
- Department of Nephrology, Second Hospital, Jilin University, Changchun, Jilin, China
| | - Xiaonong Chen
- Department of Nephrology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Bicheng Liu
- Institute of Nephrology, Zhongda Hospital, Southeast University School of Medicine, Nanjing, Jiangsu, China
| | - Yongcheng He
- Department of Nephrology, Shenzhen Hengsheng Hospital, Shenzhen, Guangdong, China
| | - Jing Li
- Department of Nephrology, The First Affiliated Hospital of Xinjiang Medical University, Ürümqi, China
| | | | | | - Zhangsuo Liu
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhihong Liu
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, Nanjing, Jiangsu, China
| |
Collapse
|
|
27
|
de la Fuente-Mancera JC, Forado-Bentar I, Farrero M. Management of long-term cardiovascular risk factors post organ transplant. Curr Opin Organ Transplant 2022; 27:29-35. [PMID: 34939962 DOI: 10.1097/mot.0000000000000950] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
PURPOSE OF REVIEW Cardiovascular disease is one of the leading causes of death in solid organ transplant (SOT) recipients. Early identification of cardiovascular risk factors and their adequate management in this population is key for prevention and improved outcomes. RECENT FINDINGS Approximately 80% of SOT present one or more cardiovascular risk factors, with increasing prevalence with time posttransplantation. They are due to the interplay of pretransplant conditions and metabolic consequences of immunosuppressive agents, mainly corticosteroids and calcineurin inhibitors. Among the pharmacological management strategies, statins have shown an important protective effect in SOT. SUMMARY Strict surveillance of cardiovascular risk factors is recommended in SOT due to their high prevalence and prognostic implications. Further studies on the best managements strategies in this population are needed.
Collapse
|
|
28
|
Karolin A, Escher G, Rudloff S, Sidler D. Nephrotoxicity of Calcineurin Inhibitors in Kidney Epithelial Cells is Independent of NFAT Signaling. Front Pharmacol 2022; 12:789080. [PMID: 35140605 PMCID: PMC8819135 DOI: 10.3389/fphar.2021.789080] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 12/29/2021] [Indexed: 01/01/2023] Open
Abstract
Background: Calcineurin inhibitors (CNIs) such as cyclosporine A and tacrolimus are commonly used after renal transplantation to suppress the immune system. In lymphoid cells, cyclosporine A acts via the calcineurin/nuclear factor of activated T-cell (NFAT) axis. In non-lymphoid cells, such as kidney epithelial cells, cyclosporine A induces calcineurin inhibitor toxicity. It is unknown via which off-targets cyclosporine A induces calcineurin inhibitor toxicity in kidney epithelial cells. Methods: To measure a compound’s potential to induce nephrotoxicity, the expression of the surrogate marker Fn14 was measured by flow cytometry. Compounds were tested for their potential to induce Fn14 either chemically or plasmid-mediated. Mice were injected with various compounds, and changes in nephrotoxic gene expression levels of the kidney epithelial cells were then analyzed. Results: Fn14 is specifically upregulated due to calcineurin inhibitor toxicity inducing agents. Inhibition of the NFAT axis showed no increase of the Fn14 expression on the surface of kidney cells. However, inhibition of p38 MAPK, phosphoinositide-3-kinase (PI3K)/Akt, protein kinase C (PKC), and inhibitor of nuclear factor-κB (IκB) kinase (IKK) showed clear induction of Fn14 and increased expressions of nephrotoxic, inflammatory, and fibrotic genes in vitro and in vivo. Conclusions: These findings show that cyclosporine A acts independently of NFAT on kidney epithelial cells. Moreover, inhibition of serine/threonine protein kinases mimics cyclosporine A’s activity on kidney epithelial cells. This mimicking effect indicates that these protein kinases are off-targets of cyclosporine A and damage structural renal cells when inhibited and therefore contributes likely to the development and progression of calcineurin inhibitor toxicity.
Collapse
Affiliation(s)
- Andrea Karolin
- Department for Nephrology and Hypertension, University Hospital Insel Bern, Bern, Switzerland
- Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
| | - Geneviève Escher
- Department for Nephrology and Hypertension, University Hospital Insel Bern, Bern, Switzerland
| | - Stefan Rudloff
- Department for Nephrology and Hypertension, University Hospital Insel Bern, Bern, Switzerland
| | - Daniel Sidler
- Department for Nephrology and Hypertension, University Hospital Insel Bern, Bern, Switzerland
- *Correspondence: Daniel Sidler,
| |
Collapse
|
|
29
|
Dugbartey GJ, Sener A. Organ Toxicity by Immunosuppressive Drugs in Solid Organ Transplantation. RECENT ADVANCES IN THERAPEUTIC DRUG MONITORING AND CLINICAL TOXICOLOGY 2022:255-271. [DOI: 10.1007/978-3-031-12398-6_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
30
|
Yılmaz EA, Özdemir Ö. Solid organ transplantations and COVID-19 disease. World J Transplant 2021; 11:503-511. [PMID: 35070786 PMCID: PMC8713305 DOI: 10.5500/wjt.v11.i12.503] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 08/04/2021] [Accepted: 11/15/2021] [Indexed: 02/06/2023] Open
Abstract
Tens of thousands of people worldwide became infected with severe acute respiratory syndrome coronavirus-2. Death rate in the general population is about 1%-6%, but this rate rises up to 15% in those with comorbidities. Recent publications showed that the clinical progression of this disease in organ recipients is more destructive, with a fatality rate of up to 14%-25%. We aimed to review the effect of the pandemic on various transplantation patients. Coronavirus disease 2019 (COVID-19) has not only interrupted the lives of waiting list patients’; it has also impacted transplantation strategies, transplant surgeries and broken donation chains. COVID-19 was directly and indirectly accountable for a 73% surplus in mortality of this population as compared to wait listed patients in earlier years. The impact of chronic immunosuppression on outcomes of COVID-19 remains unclear but understanding the immunological mechanisms related to the virus is critically important for the lifetime of transplantation and immune suppressed patients. It is hard to endorse changing anti-rejection therapy, as the existing data evaluation is not adequate to advise substituting tacrolimus with cyclosporine during severe COVID-19 disease.
Collapse
Affiliation(s)
- Emine Aylin Yılmaz
- Division of Pediatric Allergy and Immunology, Sakarya University Medical Faculty, Adapazarı 54100, Sakarya, Turkey
| | - Öner Özdemir
- Division of Pediatric Allergy and Immunology, Sakarya University Medical Faculty, Adapazarı 54100, Sakarya, Turkey
| |
Collapse
|