|
1
|
Marmion DJ, Deng P, Hiller BM, Lewis RL, Harms LJ, Cameron DL, Nolta JA, Kordower JH, Fink KD, Wakeman DR. Long-Term Engraftment of Cryopreserved Human Neurons for In Vivo Disease Modeling in Neurodegenerative Disease. BIOLOGY 2025; 14:217. [PMID: 40001985 PMCID: PMC11852092 DOI: 10.3390/biology14020217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/24/2025] [Revised: 02/12/2025] [Accepted: 02/14/2025] [Indexed: 02/27/2025]
Abstract
The transplantation of human neurons into the central nervous system (CNS) offers transformative opportunities for modeling neurodegenerative diseases in vivo. This study evaluated the survival, integration, and functional properties of cryopreserved forebrain GABAergic neurons (iGABAs) derived from human induced pluripotent stem cells (iPSCs) across three species used in translational research. iGABAs were stereotactically injected into the striatum of Sprague-Dawley rats, immunodeficient RNU rats, R6/2 Huntington's disease (HD) mice, wild-type controls, and Cynomolgus monkeys. Post-transplantation, long-term assessments revealed robust neuronal survival, extensive neurite outgrowth, and integration with host CNS environments. In immunodeficient rats, iGABAs innervated the neuraxis, extending from the prefrontal cortex to the midbrain, while maintaining mature neuronal phenotypes without uncontrolled proliferation. Similarly, grafts in nonhuman primates showed localized survival and stable phenotype at one month. In the neurodegenerative milieu of HD mice, iGABAs survived up to six months, projecting into the host striatum and white matter, with evidence of mutant huntingtin aggregates localized within the graft, indicating pathological protein transfer. These findings underscore the utility of cryopreserved iGABAs as a reproducible, scalable model for disease-specific CNS investigations and mechanistic studies of proteinopathic propagation. This work establishes a critical platform for studying neurodegenerative diseases and developing therapeutic interventions.
Collapse
Affiliation(s)
- David J. Marmion
- Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA
- Department of Neurobiology, Barrow Neurological Institute, Phoenix, AZ 85013, USA
| | - Peter Deng
- Stem Cell Program, Department of Neurology, Institute for Regenerative Cures, University of California Davis, Sacramento, CA 95817, USA; (P.D.)
| | - Benjamin M. Hiller
- Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA
| | | | - Lisa J. Harms
- FujiFilm Cellular Dynamics Inc., Madison, WI 53711, USA
| | - David L. Cameron
- Stem Cell Program, Department of Neurology, Institute for Regenerative Cures, University of California Davis, Sacramento, CA 95817, USA; (P.D.)
| | - Jan A. Nolta
- Stem Cell Program, Department of Neurology, Institute for Regenerative Cures, University of California Davis, Sacramento, CA 95817, USA; (P.D.)
| | - Jeffrey H. Kordower
- Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA
- Banner Neurodegenerative Disease Research Center, Arizona State University, Tempe, AZ 85281, USA
| | - Kyle D. Fink
- Stem Cell Program, Department of Neurology, Institute for Regenerative Cures, University of California Davis, Sacramento, CA 95817, USA; (P.D.)
| | - Dustin R. Wakeman
- Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA
- Department of Psychiatry, Yale University, New Haven, CT 06511, USA
| |
Collapse
|
|
2
|
Kamogashira T, Nakada T, Kanaya K. A Study of Dizziness or Vertigo Cases Associated with Inflammatory Bowel Disease (Crohn's Disease and Ulcerative Colitis) in a Vertigo Outpatient Clinic. J Clin Med 2025; 14:341. [PMID: 39860349 PMCID: PMC11765578 DOI: 10.3390/jcm14020341] [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: 12/05/2024] [Revised: 12/31/2024] [Accepted: 01/06/2025] [Indexed: 01/27/2025] Open
Abstract
Background/Objectives: Dizziness and vertigo are reported in about half of patients with inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). Orthostatic dysregulation (OD) is recognized as one of the comorbidities that causes dizziness or vertigo with IBD. Our hospital is affiliated with the Inflammatory Bowel Disease Center, which specializes in diagnosing and treating IBD, so cases with dizziness or vertigo symptoms associated with IBD are sometimes referred to our department, a type of department which is rare in other facilities. The objective of this study is to evaluate IBD cases with dizziness or vertigo symptoms referred to a vertigo outpatient clinic in terms of vestibular function and OD. Methods: The subjects were 221 patients who were referred to the vertigo outpatient clinic of our department from March 2021 to September 2024. Results: Of the 221 patients, 9 cases had CD and 1 case had UC. OD complications were significantly more common in the IBD group than in the non-IBD group, whereas complications of psychogenic vertigo or migraine were not significantly different between groups, and there was no difference in vestibular dysfunction between groups. OD was a complication in all cases using ustekinumab. Conclusions: An orthostatic test will be valuable for diagnosing OD in IBD patients with dizziness or vertigo symptoms.
Collapse
Affiliation(s)
- Teru Kamogashira
- Department of Otolaryngology, Japan Community Healthcare Organization Tokyo Yamate Medical Center, Hyakunin-cho 3-22-1, Shinjuku-ku 169-0073, Tokyo, Japan
| | | | | |
Collapse
|
|
3
|
Yen NTH, Tien NTN, Anh NTV, Le QV, Eunsu C, Kim HS, Moon KS, Nguyen HT, Kim DH, Long NP. Cyclosporine A-induced systemic metabolic perturbations in rats: A comprehensive metabolome analysis. Toxicol Lett 2024; 395:50-59. [PMID: 38552811 DOI: 10.1016/j.toxlet.2024.03.009] [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: 11/07/2023] [Revised: 03/12/2024] [Accepted: 03/26/2024] [Indexed: 04/11/2024]
Abstract
A better understanding of cyclosporine A (CsA)-induced nephro- and hepatotoxicity at the molecular level is necessary for safe and effective use. Utilizing a sophisticated study design, this study explored metabolic alterations after long-term CsA treatment in vivo. Rats were exposed to CsA with 4, 10, and 25 mg/kg for 4 weeks and then sacrificed to obtain liver, kidney, urine, and serum for untargeted metabolomics analysis. Differential network analysis was conducted to explore the biological relevance of metabolites significantly altered by toxicity-induced disturbance. Dose-dependent toxicity was observed in all biospecimens. The toxic effects were characterized by alterations of metabolites related to energy metabolism and cellular membrane composition, which could lead to the cholestasis-induced accumulation of bile acids in the tissues. The unfavorable impacts were also demonstrated in the serum and urine. Intriguingly, phenylacetylglycine was increased in the kidney, urine, and serum treated with high doses versus controls. Differential correlation network analysis revealed the strong correlations of deoxycytidine and guanosine with other metabolites in the network, which highlighted the influence of repeated CsA exposure on DNA synthesis. Overall, prolonged CsA administration had system-level dose-dependent effects on the metabolome in treated rats, suggesting the need for careful usage and dose adjustment.
Collapse
Affiliation(s)
- Nguyen Thi Hai Yen
- Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan 47392, Republic of Korea
| | - Nguyen Tran Nam Tien
- Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan 47392, Republic of Korea
| | - Nguyen Thi Van Anh
- Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan 47392, Republic of Korea
| | - Quoc-Viet Le
- Faculty of Pharmacy, Ton Duc Thang University, Ho Chi Minh City 700000, Vietnam
| | - Cho Eunsu
- Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan 47392, Republic of Korea
| | - Ho-Sook Kim
- Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan 47392, Republic of Korea
| | - Kyoung-Sik Moon
- Korea Institute of Toxicology, Daejeon 34114, Republic of Korea
| | - Huy Truong Nguyen
- Faculty of Pharmacy, Ton Duc Thang University, Ho Chi Minh City 700000, Vietnam
| | - Dong Hyun Kim
- Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan 47392, Republic of Korea.
| | - Nguyen Phuoc Long
- Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, Busan 47392, Republic of Korea.
| |
Collapse
|
|
4
|
Verona P, Edwards J, Hubert K, Avorio F, Re VL, Di Stefano R, Carollo A, Johnson H, Provenzani A. Tacrolimus-Induced Neurotoxicity After Transplant: A Literature Review. Drug Saf 2024; 47:419-438. [PMID: 38353884 DOI: 10.1007/s40264-024-01398-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/18/2024] [Indexed: 04/17/2024]
Abstract
Tacrolimus, a calcineurin inhibitor, is an immunosuppressant used globally to prevent rejection after organ transplantation. Although it significantly improves outcomes for solid organ transplant patients, it is associated with various side effects such as nephrotoxicity and neurotoxicity. Tacrolimus-induced neurotoxicity is frequently encountered in clinical practice and can present with a variety of symptoms that may occur even at therapeutic levels. Although tacrolimus-induced neurotoxicity is well documented, there is limited literature available on pharmacologic management. Twenty-eight case reports of tacrolimus-induced neurotoxicity were identified and analyzed in addition to other literature including reviews, retrospective studies, and animal model studies. The severity of cases of tacrolimus-induced neurotoxicity reported ranged from mild symptoms that could be managed with symptomatic treatment to conditions such as posterior reversible encephalopathy syndrome and chronic inflammatory demyelinating polyradiculoneuropathy that may require more immediate intervention. This information was utilized in addition to clinical experience to compile potential management options for prevention and treatment of neurotoxic adverse events. This review is limited by the utilization of primarily retrospective studies and case reports. The available literature on the subject is largely narrative and there are no guidelines on treatment of tacrolimus-induced neurotoxicity at the time of this research. This comprehensive review may guide further studies to investigate the pathophysiology of tacrolimus-induced neurotoxicity and to define patient-specific strategies for mitigation or minimization of neurotoxicity. This is especially important given that management of tacrolimus-induced neurotoxicity can include changes to immunosuppression that can result in an increased risk of rejection.
Collapse
Affiliation(s)
- Paige Verona
- School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA
| | - Jocelyn Edwards
- School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA
| | - Kassidy Hubert
- School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA
| | - Federica Avorio
- Neurology Unit, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (ISMETT), Palermo, Italy
| | - Vincenzina Lo Re
- Neurology Unit, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (ISMETT), Palermo, Italy
| | - Roberta Di Stefano
- Clinical Pharmacy Service, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (ISMETT), Via E.Tricomi n. 5, 90127, Palermo, Italy
| | - Anna Carollo
- Clinical Pharmacy Service, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (ISMETT), Via E.Tricomi n. 5, 90127, Palermo, Italy
| | - Heather Johnson
- Department of Pharmacy and Therapeutics, University of Pittsburgh School of Pharmacy, 3501 Terrace Street, Pittsburgh, PA, USA
| | - Alessio Provenzani
- Clinical Pharmacy Service, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (ISMETT), Via E.Tricomi n. 5, 90127, Palermo, Italy.
| |
Collapse
|
|
5
|
Wilson NK, Kataria AD. Immunosuppression in solid organ-transplant recipients and impact on nutrition support. Nutr Clin Pract 2024; 39:109-116. [PMID: 38030572 DOI: 10.1002/ncp.11099] [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: 09/15/2023] [Revised: 10/28/2023] [Accepted: 11/06/2023] [Indexed: 12/01/2023] Open
Abstract
A key component to nutrition support is to consider immunosuppressive agents, the interaction with nutrients, and how the side effects of the medications influence nutrition support. The immunosuppression of the solid organ-transplant recipient involves the individualized titration of multiple therapeutic agents to prevent allorecognition and, thus, rejection of the transplanted organ. Induction immunosuppression includes the agents used at the time of transplant to prevent early rejection. Maintenance immunosuppression typically consists of oral medications taken for life. Regular therapeutic monitoring of immunosuppression is necessary to balance the risk of rejection with that of infections and malignancy. In the acute-care setting, multidisciplinary collaboration, including pharmacy and nutrition, is needed to optimize the route of administration, titration, and side effects of immunosuppression. Long-term nutrition management after transplant is also vital to prevent exacerbating adverse effects of immunosuppressive therapies, including diabetes mellitus, hypertension, dyslipidemia, obesity, and bone loss. This review summarizes common immunosuppressive agents currently utilized in solid organ-transplant recipients and factors that may influence decisions on nutrition support.
Collapse
Affiliation(s)
- Nicole K Wilson
- Department of Pharmacy, Baylor University Medical Center, Dallas, Texas, USA
| | - Ann D Kataria
- Department of Pharmacy, Baylor University Medical Center, Dallas, Texas, USA
| |
Collapse
|
|
6
|
Abderahmene A, Khalij Y, Moussa A, Ammar M, Ellouz A, Amor D, Abbes H, Ganouni MR, Sahtout W, Chouchene S, Omezzine A, Zellama D, Bouslama A. The pharmacogenetics of tacrolimus in renal transplant patients: association with tremors, new-onset diabetes and other clinical events. THE PHARMACOGENOMICS JOURNAL 2024; 24:3. [PMID: 38253626 DOI: 10.1038/s41397-024-00323-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/12/2023] [Accepted: 01/04/2024] [Indexed: 01/24/2024]
Abstract
Our study is the first study to investigate the effect of SNPs in CYP3A5, CYP3A4, ABCB1 and POR genes on the incidence of tremors, nephrotoxicity, and diabetes mellitus. A total of 223 renal transplant patients receiving tacrolimus and mycophenolate mofetil (MMF) were recruited. Both adults and children patients participated in the study. Genotyping was performed using PROFLEX-PCR followed by RFLP. MPA and tacrolimus plasma concentrations were measured by immunoassay. The AUC0-12h of MMF was estimated by a Bayesian method. We found a statistically significant association between the CYP3A5*3 and CYP3A4*1B genotypes and the tacrolimus exposure. We found a lower occurrence of nephrotoxicity (p = 0.03), tremor (p = 0.01), and new-onset diabetes (p = 0.002) associated with CYP3A5*1 allele. The CYP3A4*1B allele was significantly associated with a lower occurrence of new-onset diabetes (p = 0.026). The CYP3A5*1 allele was significantly associated with an increased risk of acute and chronic rejection (p = 0.03 and p < 0.001, respectively). Our results support the usefulness of tacrolimus pharmacokinetics in pre-kidney transplant assessments.
Collapse
Affiliation(s)
- Amani Abderahmene
- Biochemistry Department, LR12SP11, Sahloul University Hospital, Street Route Ceinture Sahloul, 4054, Sousse, Tunisia.
- University of Monastir, Faculty of Pharmacy of Monastir, Street Ibn Sina, 5000, Monastir, Tunisia.
| | - Yassine Khalij
- Biochemistry Department, LR12SP11, Sahloul University Hospital, Street Route Ceinture Sahloul, 4054, Sousse, Tunisia
- University of Monastir, Faculty of Pharmacy of Monastir, Street Ibn Sina, 5000, Monastir, Tunisia
| | - Amira Moussa
- Biochemistry Department, LR12SP11, Sahloul University Hospital, Street Route Ceinture Sahloul, 4054, Sousse, Tunisia
- University of Monastir, Faculty of Pharmacy of Monastir, Street Ibn Sina, 5000, Monastir, Tunisia
| | - Meriam Ammar
- Biochemistry Department, LR12SP11, Sahloul University Hospital, Street Route Ceinture Sahloul, 4054, Sousse, Tunisia
- University of Monastir, Faculty of Pharmacy of Monastir, Street Ibn Sina, 5000, Monastir, Tunisia
| | - Amel Ellouz
- Biochemistry Department, LR12SP11, Sahloul University Hospital, Street Route Ceinture Sahloul, 4054, Sousse, Tunisia
- University of Monastir, Faculty of Pharmacy of Monastir, Street Ibn Sina, 5000, Monastir, Tunisia
| | - Dorra Amor
- Biochemistry Department, LR12SP11, Sahloul University Hospital, Street Route Ceinture Sahloul, 4054, Sousse, Tunisia
- University of Monastir, Faculty of Pharmacy of Monastir, Street Ibn Sina, 5000, Monastir, Tunisia
| | - Houwaida Abbes
- Biochemistry Department, LR12SP11, Sahloul University Hospital, Street Route Ceinture Sahloul, 4054, Sousse, Tunisia
- University of Monastir, Faculty of Pharmacy of Monastir, Street Ibn Sina, 5000, Monastir, Tunisia
| | - Mohamed Rayen Ganouni
- Biochemistry Department, LR12SP11, Sahloul University Hospital, Street Route Ceinture Sahloul, 4054, Sousse, Tunisia
- University of Monastir, Faculty of Pharmacy of Monastir, Street Ibn Sina, 5000, Monastir, Tunisia
| | - Wissal Sahtout
- Nephrology Department, Sahloul University Hospital, Street Route Ceinture Sahloul, 4054, Sousse, Tunisia
| | - Saoussen Chouchene
- Hematology Department, Fattouma Bourguiba University Hospital, 5000, Monastir, Tunisia
| | - Asma Omezzine
- Biochemistry Department, LR12SP11, Sahloul University Hospital, Street Route Ceinture Sahloul, 4054, Sousse, Tunisia
- University of Monastir, Faculty of Pharmacy of Monastir, Street Ibn Sina, 5000, Monastir, Tunisia
| | - Dorsaf Zellama
- Nephrology Department, Sahloul University Hospital, Street Route Ceinture Sahloul, 4054, Sousse, Tunisia
| | - Ali Bouslama
- Biochemistry Department, LR12SP11, Sahloul University Hospital, Street Route Ceinture Sahloul, 4054, Sousse, Tunisia
- University of Monastir, Faculty of Pharmacy of Monastir, Street Ibn Sina, 5000, Monastir, Tunisia
| |
Collapse
|
|
7
|
Sunakawa H, Mizoi K, Takahashi R, Takahashi S, Ogihara T. Impact of P-Glycoprotein-Mediated Drug-Endogenous Substrate Interactions on Androgen and Blood-Brain Barrier Permeability. J Pharm Sci 2024; 113:228-234. [PMID: 37898165 DOI: 10.1016/j.xphs.2023.10.034] [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: 05/29/2023] [Revised: 10/24/2023] [Accepted: 10/24/2023] [Indexed: 10/30/2023]
Abstract
This report focuses on pharmacokinetic drug-endogenous substrate interactions (DEIs). We hypothesized that P-glycoprotein (P-gp)-mediated DEI might affect androgen kinetics, especially its blood-brain barrier (BBB) permeability. The intracellular accumulation of the endogenous substrates of P-gp, testosterone (TES) and androstenedione (ADO) was increased by several tested drugs in uptake studies using P-gp overexpressing cells, indicating that these drugs inhibit P-gp-mediated efflux of TES of ADO from the cells. In a transport study using rat BBB kit, we found that the BBB limited the penetration of TES and ADO into the central nervous system. In addition, tested drugs that cause DEI were found to increase BBB permeability of TES and ADO via P-gp inhibition. In short, this study provides new findings regarding the possibility that DEI may affect the kinetics of endogenous substrates of P-gp.
Collapse
Affiliation(s)
- Hiroki Sunakawa
- Graduate School of Pharmaceutical Sciences, Takasaki University of Health and Welfare.
| | - Kenta Mizoi
- School of Pharmacy, International University of Heath and Welfare
| | - Reiko Takahashi
- Faculty of Pharmacy, Takasaki University of Health and Welfare
| | - Saori Takahashi
- Faculty of Pharmacy, Takasaki University of Health and Welfare
| | - Takuo Ogihara
- Graduate School of Pharmaceutical Sciences, Takasaki University of Health and Welfare; Faculty of Pharmacy, Takasaki University of Health and Welfare
| |
Collapse
|
|
8
|
King CP, Cossart AR, Isbel NM, Campbell SB, Staatz CE. The association between tacrolimus exposure and tremor, headache and insomnia in adult kidney transplant recipients: A systematic review. Transplant Rev (Orlando) 2024; 38:100815. [PMID: 38071930 DOI: 10.1016/j.trre.2023.100815] [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: 10/23/2023] [Revised: 11/28/2023] [Accepted: 11/30/2023] [Indexed: 01/08/2024]
Abstract
PURPOSE Tremor, headache and insomnia have been linked to the immunosuppressant, tacrolimus. The aim of this systematic review was to determine if there is a correlation between tacrolimus exposure and new-onset tremor, headache and insomnia experienced by adult kidney transplant recipients. METHODS PubMed, Embase, Cochrane Library and CINAHL databases were searched up to 11 April 2023 for published studies which reported on tacrolimus exposure in adult kidney transplant recipients, alongside information on treatment-emergent neurologic manifestations, including tremor, headache and insomnia. Review articles, case studies, conference abstracts and articles not published in English in peer-reviewed journals were excluded. The Physiotherapy Evidence Database and Newcastle-Ottawa Quality Assessment Scales were used to assess risk of bias. Extracted data was analysed via a narrative synthesis. RESULTS Eighteen studies involving 4030 patients in total were included in the final analysis. These comprised five randomised control trials and thirteen observational studies. Studies failed to find significant association between tacrolimus trough concentrations in whole blood and the incidence of neurologic side effects such as tremor, headache and insomnia; however, in one study the incidence of toxicity requiring a dose reduction increased with increasing, supratherapeutic targeted levels. Females, especially Black females, and older age were positively associated with the prevalence of neurologic adverse effects. Results were conflicting regarding whether extended-release formulations were associated with fewer neurologic complications than immediate-release formulations. CONCLUSION The varied study designs and criteria for reporting tremor, headache and insomnia impacted on the quality of the data for exploring the relationship between tacrolimus exposure and the onset of neurologic manifestations experienced after kidney transplantation. Studies that examine defined neurologic complications as the primary outcome, and that consider novel markers of tacrolimus exposure while assessing the potential contribution of multiple covariate factors, are required.
Collapse
Affiliation(s)
- Catherine P King
- School of Pharmacy, The University of Queensland, Brisbane, QLD, Australia.
| | - Amelia R Cossart
- School of Pharmacy, The University of Queensland, Brisbane, QLD, Australia
| | - Nicole M Isbel
- Department of Nephrology, The Princess Alexandra Hospital, Brisbane, QLD, Australia
| | - Scott B Campbell
- Department of Nephrology, The Princess Alexandra Hospital, Brisbane, QLD, Australia
| | - Christine E Staatz
- School of Pharmacy, The University of Queensland, Brisbane, QLD, Australia
| |
Collapse
|
|
9
|
Panagopoulos GN, Megaloikonomos PD, Mitsiokapa EA, Bami M, Agrogiannis G, Johnson EO, Soucacos PN, Papagelopoulos PJ, Mavrogenis AF. Adipose-Derived Stem Cells and Tacrolimus Improve Nerve Regeneration in a Rat Sciatic Nerve Defect Model. Orthopedics 2023; 46:e353-e361. [PMID: 37052592 DOI: 10.3928/01477447-20230407-01] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/14/2023]
Abstract
This study compared the effect of undifferentiated adipose-derived stem cells (ADSCs) vs tacrolimus (FK506) in peripheral nerve regeneration in a rat sciatic nerve complete transection model. Forty Wistar rats were equally distributed in four groups. In the SHAM surgery group, the sciatic nerve was exposed and no further intervention was done. In the conduit-alone group (the SLN group), a 10-mm nerve gap was created and bridged with a fibrin conduit filled in with normal saline. In the FK506 group, the fibrin conduit was injected with soluble FK506. In the ADSC group, the conduit was impregnated with undifferentiated ADSCs. Nerve regeneration was assessed by means of walking track analysis, electromyography, and neurohistomorphometry. Clinically and microscopically, nerve regeneration was achieved in all groups at 12 weeks. Walking track analysis confirmed functional recovery in the FK506 and ADSC groups, but there was no difference between them. Recovery in function was also achieved in the SLN group, but it was inferior (P<.05). Electromyography demonstrated superior nerve regeneration in the FK506 and ADSC groups compared with the SLN group (P<.05), with no difference between the FK506 and ADSC groups. Similarly, histology showed no difference between the FK506 and ADSC groups, although both outperformed the SLN group (P<.05). No complications were observed. Successful peripheral nerve regeneration can be accomplished after a 10-mm nerve defect treated with nerve conduits. Superior nerve regeneration may be expected when the conduits are loaded with undifferentiated ADSCs or FK506, with similar outcomes for ADSCs and FK506. [Orthopedics. 2023;46(6):e353-e361.].
Collapse
|
|
10
|
Provenzani A, Re VL. Tacrolimus-induced akinetic mutism and persistent dysarthria following orthotopic liver transplantation. Neurol Sci 2023; 44:2983-2984. [PMID: 36949300 DOI: 10.1007/s10072-023-06760-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 03/15/2023] [Indexed: 03/24/2023]
Affiliation(s)
- Alessio Provenzani
- Clinical Pharmacy Service, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (ISMETT), Palermo, Italy.
| | - Vincenzina Lo Re
- Neurology Unit, Mediterranean Institute for Transplantation and Advanced Specialized Therapies (ISMETT), Palermo, Italy
| |
Collapse
|
|
11
|
Lv B, Liu L, Liu X, Huang M, Chen X, Tang K, Wang C, Chen P. Incidence, clinical features and risk factors of tacrolimus induced idiosyncratic liver injury in renal transplant recipients: A nested case-control study. Front Pharmacol 2023; 14:1126765. [PMID: 36992828 PMCID: PMC10040645 DOI: 10.3389/fphar.2023.1126765] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2022] [Accepted: 03/03/2023] [Indexed: 03/15/2023] Open
Abstract
Rare data reported tacrolimus-induced liver injury (tac-DILI) in real world. We performed a nested case-control analysis of 1,010 renal transplant recipients. Recipients with tac-DILI were randomly matched at a ratio of 1:4 by the year of admission to the remaining recipients without tac-DILI to explore risk factors. The incidence of tac-DILI was 8.9% (95% CI = 7.2–10.7%). The most common type was cholestatic pattern (6.7%, 95% CI = 5.2–8.3%), followed by hepatocellular (1.6%, 95% CI = 0.8–2.4%) and mixed patterns (0.6%, 95% CI = 0.1–1.1%). 98.9% of recipients with tac-DILI have mild severity. The latency period were 42.0 (range, 21.5–99.8 days), 14.0 (range, 9.0–80.3 days), 16.0 (range, 11.5–24.5 days), and 49.0 days (range, 28.0–105.6 days) for total, hepatocellular, mixed, and cholestatic patterns, respectively. Baseline ALP level (OR = 1.015, 95% CI = 1.006–1.025, p = 0.002), age (OR = 0.971, 95% CI = 0.949–0.994, p = 0.006), and body weight (OR = 0.960, 95% CI = 0.940–0.982, p < 0.001) were independent risk factors. In conclusion, cholestatic pattern represents the most frequent type of tac-DILI. Young age, low body weight and abnormal baseline ALP level were risk factors.
Collapse
Affiliation(s)
- Binbin Lv
- Department of Pharmacy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Longshan Liu
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaoman Liu
- Department of Pharmacy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Min Huang
- Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Xiao Chen
- Department of Pharmacy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Kejing Tang
- Department of Pharmacy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Changxi Wang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- *Correspondence: Changxi Wang, ; Pan Chen,
| | - Pan Chen
- Department of Pharmacy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- *Correspondence: Changxi Wang, ; Pan Chen,
| |
Collapse
|
|
12
|
Elsedeiq M, Abdelkhalek M, Abozeid KM, Habl MS, Elmorshedi MA, Yassen AM, Emara MM. Intraoperative Optic Nerve Sheath Diameter as a Predictor of Early Tacrolimus Neurotoxicity after Living Donor Liver Transplantation. Anaesth Crit Care Pain Med 2023; 42:101178. [PMID: 36442803 DOI: 10.1016/j.accpm.2022.101178] [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: 09/13/2022] [Accepted: 11/14/2022] [Indexed: 11/27/2022]
Abstract
BACKGROUND During liver transplantation, graft reperfusion triggers cerebral hyperemia, increases intracranial pressure, and disrupts the blood-brain barrier, thereby increasing the risk for immunosuppression neurotoxicity. Therefore, we tested the intraoperative optic nerve sheath diameter (ONSD) for predicting tacrolimus neurotoxicity after liver transplantation. BASIC PROCEDURES We prospectively included 100 adult patients who underwent living donor liver transplantation. The ultrasonographic ONSD 5 min after reperfusion was used as the index test, whereas the occurrence of early tacrolimus neurotoxicity was used as the reference. The area under the receiver operating characteristic curve (AUROC) was used to estimate the ONSD prediction accuracy. We reported the specificity and sensitivity of ONSD 5 and 30 min after reperfusion. Cutoffs were derived from the ROC curves. In addition, we used regression to control for confounders while testing the association between the ONSD and tacrolimus neurotoxicity. MAIN FINDINGS The AUROC at T3 was 0.74 (95% confidence interval (CI), 0.63-0.85, P < 0.001). An ONSD of ≥6.4 mm at T3 had an 86% sensitivity (95% CI, 68%-96%) and 53% specificity (95% CI, 41%-65%). An ONSD of ≥6.4 mm at T3 had an adjusted odds ratio for tacrolimus neurotoxicity of 6.3 (95% CI, 1.9-21, P = 0.003). CONCLUSIONS This data indicates that intraoperative ultrasonic ONSD after reperfusion can predict tacrolimus neurotoxicity after liver transplantation. TRIAL REGISTRATION NCT03799770; registered on January 1st, 2019.
Collapse
Affiliation(s)
- Mahmoud Elsedeiq
- Department of Anesthesiology and Intensive Care and Pain Medicine - Mansoura University, Faculty of Medicine, Mansoura, Egypt; Liver Transplantation Program, Gastrointestinal Surgery Center, Mansoura University, Mansoura, Egypt
| | - Mostafa Abdelkhalek
- Department of Anesthesiology and Intensive Care and Pain Medicine - Mansoura University, Faculty of Medicine, Mansoura, Egypt; Liver Transplantation Program, Gastrointestinal Surgery Center, Mansoura University, Mansoura, Egypt
| | - Kareem M Abozeid
- Department of Anesthesiology and Intensive Care and Pain Medicine - Mansoura University, Faculty of Medicine, Mansoura, Egypt; Liver Transplantation Program, Gastrointestinal Surgery Center, Mansoura University, Mansoura, Egypt
| | - Mohamed S Habl
- Liver Transplantation Program, Gastrointestinal Surgery Center, Mansoura University, Mansoura, Egypt; Department of Internal Medicine, Hepatology and Gastroenterology unit - Mansoura University, Faculty of Medicine, Mansoura, Egypt
| | - Mohamed A Elmorshedi
- Department of Anesthesiology and Intensive Care and Pain Medicine - Mansoura University, Faculty of Medicine, Mansoura, Egypt; Liver Transplantation Program, Gastrointestinal Surgery Center, Mansoura University, Mansoura, Egypt
| | - Amr M Yassen
- Department of Anesthesiology and Intensive Care and Pain Medicine - Mansoura University, Faculty of Medicine, Mansoura, Egypt; Liver Transplantation Program, Gastrointestinal Surgery Center, Mansoura University, Mansoura, Egypt
| | - Moataz Maher Emara
- Department of Anesthesiology and Intensive Care and Pain Medicine - Mansoura University, Faculty of Medicine, Mansoura, Egypt; Liver Transplantation Program, Gastrointestinal Surgery Center, Mansoura University, Mansoura, Egypt.
| |
Collapse
|
|
13
|
Bugallo-Carrera C, Facal D, Domínguez-Lenogue C, Álvarez-Vidal V, Gandoy-Crego M, Caamaño-Ponte J. Neuropsychiatric Symptoms after Liver Transplantation in a 65-Year-Old Male Patient. Brain Sci 2022; 12:1721. [PMID: 36552180 PMCID: PMC9776108 DOI: 10.3390/brainsci12121721] [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: 11/05/2022] [Revised: 12/07/2022] [Accepted: 12/10/2022] [Indexed: 12/23/2022] Open
Abstract
The development of immunosuppressants has been key for the advancement of solid organ transplant surgery. Specifically, cyclosporine, tacrolimus, or everolimus have significantly increased the survival rate of patients by reducing the risk of a rejection of the transplanted organ and limiting graft-versus-host disease. We report the case of a 65-year-old man who, after undergoing a liver transplantation and receiving an immunosuppressive treatment with cyclosporine and everolimus, presented severe obsessive, psychotic, and behavioral symptoms over the past three years, and describe the pharmacological and non-pharmacological interventions implemented against these symptoms. In this case, the immunosuppressants used have been cyclosporine and, preferably, everolimus. On the other hand, potential adverse reactions to the treatment have been observed, including neuropsychiatric symptoms such as tremor, anxiety, dysthymia, psychosis, and behavioral disorders, which make it necessary to use corrective psychoactive drugs such as benzodiazepines, antidepressants, and antipsychotics, combined with non-pharmacological interventions. A transversal approach, from the medical and psychosocial disciplines, facilitates success in managing neuropsychiatric symptoms after soft organ transplants.
Collapse
Affiliation(s)
- Cesar Bugallo-Carrera
- Asociación de Familiares de Enfermos de Alzheimer de Fisterra e Soneira—Afafes. Cee, 15270 A Coruña, Spain
- Department of Developmental Psychology, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain
| | - David Facal
- Department of Developmental Psychology, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain
| | - Cristina Domínguez-Lenogue
- Asociación de Familiares de Enfermos de Alzheimer de Fisterra e Soneira—Afafes. Cee, 15270 A Coruña, Spain
| | - Vanessa Álvarez-Vidal
- Hospital de Día de Procesos, Servicio de Geriatría, Hospital Universitario Lucus Augusti, 27003 Lugo, Spain
| | - Manuel Gandoy-Crego
- Department of Psychiatry, Radiology, Public Health, Nursing and Medicine, University of Santiago de Compostela, 15782 Santiago de Compostela, Spain
| | | |
Collapse
|
|
14
|
Abstract
The last 2 decades have witnessed considerable advances in our understanding of thrombotic thrombocytopenic purpura (TTP). However, there is still some ambiguity regarding the precise nature of this disease, especially with respect to nervous system involvement and the correct nomenclature. This article seeks to summarize the clinical manifestations of TTP and the associated diseases. We describe TTP complicated with cerebrovascular disease, spinal cord injury, posterior reversible encephalopathy syndrome (PRES), anxious-depressive symptoms, and cognitive decline. TTP with spinal cord injury is rarely reported. For better clarity, we discuss the case of a 57-year-old woman who was diagnosed with neuromyelitis optica spectrum disease (NMOSD) with atypical TTP. The concurrent occurrence of NMOSD and TTP in this patient is consistent with the characteristics of acquired autoimmunity. We highlight the importance of early recognition of TTP in patients with atypical presentation who may not have the expected clinical or laboratory findings. This is particularly important in TTP patients with other concomitant autoimmune diseases or age-related comorbid conditions.
Collapse
Affiliation(s)
- Hui Zhu
- Department of Neurology, The First Hospital, Jilin University, Changchun, China
| | - Jing-Yao Liu
- Department of Neurology, The First Hospital, Jilin University, Changchun, China
- * Correspondence: Jing-Yao Liu, Department of Neurology, The First Hospital, Jilin University, Jilin Road, No. 3302, Changchun 130031, China (e-mail: , )
| |
Collapse
|
|
15
|
Hotta K, Hirose T, Kawai T. Clinical trials for renal allograft tolerance induction through combined hematopoietic stem cell transplantation: A narrative review. Int J Urol 2022; 29:1397-1404. [PMID: 36101964 DOI: 10.1111/iju.15035] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Accepted: 08/15/2022] [Indexed: 11/30/2022]
Abstract
During the last four decades, development of effective immunosuppressants has significantly improved short-term results of organ transplantation. However, long-term results have not been satisfactory due to chronic rejection or complications caused by immunosuppressive drugs. Therefore, induction of immunological tolerance of the transplanted organ is considered essential to improve the long-term results. Despite numerous tolerance strategies that have been successful in murine models, inducing hematopoietic chimerism through donor hematopoietic stem cell transplantation is the only method that reproducibly induces kidney allograft tolerance in nonhuman primates or humans. Combining kidney and hematopoietic stem cell transplantation to achieve allograft tolerance has now been attempted with different chimerism strategies. This review summarizes the status of current clinical trials on the induction of allograft tolerance. We also summarize recent studies to extend the chimerism approach to deceased donor transplant recipients.
Collapse
Affiliation(s)
- Kiyohiko Hotta
- Department of Urology, Hokkaido University Hospital, Sapporo, Japan
| | - Takayuki Hirose
- Department of Urology, Hokkaido University Hospital, Sapporo, Japan
| | - Tatsuo Kawai
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| |
Collapse
|
|
16
|
Model-informed Estimation of Acutely Decreased Tacrolimus Clearance and Subsequent Dose Individualization in a Pediatric Renal Transplant Patient with Posterior Reversible Encephalopathy Syndrome. Ther Drug Monit 2022; 45:376-382. [PMID: 36728342 DOI: 10.1097/ftd.0000000000001045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 07/22/2022] [Indexed: 02/03/2023]
Abstract
BACKGROUND Considerable inter-patient and inter-occasion variability has been reported in tacrolimus pharmacokinetics (PK) in the pediatric renal transplant population. The present study investigated tacrolimus PK in a 2-year-old post-renal transplant patient and a known CYP3A5 expresser who developed posterior reversible encephalopathy syndrome (PRES) and had significantly elevated tacrolimus blood concentrations during tacrolimus treatment. A model-informed PK assessment was performed to assist with precision dosing. Tacrolimus clearance was evaluated both before and after the development of PRES on post-transplant day (PTD) 26. METHODS A retrospective chart review was conducted to gather dosing data and tacrolimus concentrations, as part of a clinical pharmacology consultation service. Individual PK parameters were estimated by Bayesian estimation using a published pediatric PK model. Oral clearance (CL/F) was estimated for three distinct time periods-before CNS symptoms (PTD 25), during the PRES event (PTD 27-30), and after oral tacrolimus was re-started (PTD 93). RESULTS Bayesian estimation showed an estimated CL/F of 15.0 L/h in the days preceding the PRES event, compared to a population mean of 16.3 L/h (95% confidence interval 14.9-17.7 L/h) for CYP3A5 expressers of the same age and weight. Samples collected on PTD 27-30 yielded an estimated CL/F of 3.6 L/h, a reduction of 76%, coinciding with clinical confirmation of PRES and therapy discontinuation. On PTD 93, an additional assessment showed a stable CL/F value of 14.5 L/h one month after re-initiating tacrolimus and was used to recommend a continued maintenance dose. CONCLUSION This is the first report to demonstrate acutely decreased tacrolimus clearance in PRES, likely caused by the downregulation of metabolizing enzymes in response to inflammatory cytokines. The results suggest the ability of model-informed Bayesian estimation to characterize an acute decline in oral tacrolimus clearance after the development of PRES, and the role that PK estimation may play in supporting dose selection and individualization.
Collapse
|
|
17
|
Immunosuppressive drugs and associated complications in abdominal organ transplantation. Curr Opin Crit Care 2022; 28:208-215. [PMID: 35142726 DOI: 10.1097/mcc.0000000000000927] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE OF REVIEW Intensive care management of patients who have undergone organ transplantation of liver, small bowel, pancreas, and/or kidney requires a basic knowledge of immunosuppression principles and the management of immunosuppressive medications. This review highlights the core principles of immunosuppression management in abdominal organ transplantation with a focus on complications arising from immunosuppressive drugs, both in the immediate postoperative period and in long-term usage. RECENT FINDINGS The general principles of management of immunosuppression in the abdominal organ transplant population have remained largely unchanged. Improvements in drug monitoring coupled with improvements in knowledge of pathways involved in allograft rejection have further refined immunosuppressive therapy. Infectious and central nervous system complications remain prevalent and are common complications of immunosuppressive drug therapy. SUMMARY For the intensive care professional who cares for abdominal organ transplant recipients, a foundational knowledge of the core principles of immunosuppression management is essential. In addition, an understanding of the common immunosuppressive drug regimens and the complications associated with these regimens is required for optimal management, risk assessment, and outcomes.
Collapse
|
|
18
|
Ismail II, Abdelnabi EA, Khan R, Al-Hashel JY, Sharfuddin KM. Tacrolimus-Induced Leukoencephalopathy in a Renal Transplantation Patient. DUBAI MEDICAL JOURNAL 2022. [DOI: 10.1159/000521790] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
Tacrolimus is an immunosuppressant that is frequently used following renal transplantation. Several mild neurological side effects of tacrolimus have been reported in the literature; however, severe complications in the form of confusion, seizures, and coma are rare. Herein, we report a 16-year-old boy on tacrolimus following living-donor kidney transplant, who presented with subacute onset of hand tremors, headache, altered mental status, and progressed to akinetic mute state. He was diagnosed with tacrolimus-induced leukoencephalopathy based on findings of his magnetic resonance imaging and ruling out other possible causes. He showed clinical and radiological improvement after discontinuation of tacrolimus. Radiological features of tacrolimus-induced leukoencephalopathy are more heterogenous than commonly perceived and should be suspected in such patients. The potential neurotoxicity of tacrolimus should be recognized in patients with renal transplantation, and switching to a different immunosuppressant is warranted to prevent permanent neurological damage.
Collapse
|
|
19
|
Le Guennec L, Marois C, Demeret S, Wijdicks EFM, Weiss N. Toxic-metabolic encephalopathy in adults: Critical discussion and pragmatical diagnostic approach. Rev Neurol (Paris) 2022; 178:93-104. [PMID: 34996631 DOI: 10.1016/j.neurol.2021.11.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 11/16/2021] [Accepted: 11/17/2021] [Indexed: 10/19/2022]
Abstract
Toxic-metabolic encephalopathy (TME) results from an acute cerebral dysfunction due to different metabolic disturbances including medications or illicit-drugs. It can lead to altered consciousness, going from delirium to coma, which may require intensive care and invasive mechanical ventilation. Even if it is a life-threatening condition, TME might have an excellent prognosis if its etiology is rapidly identified and treated adequately. This review summarizes the main etiologies, their differential diagnosis, and diagnostic strategy and management of TME with a critical discussion on the definition of TME.
Collapse
Affiliation(s)
- L Le Guennec
- Sorbonne Université, AP-HP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, département de neurologie, unité de Médecine Intensive Réanimation à orientation neurologique, Paris, France; Groupe de Recherche Clinique en REanimation et Soins intensifs du Patient en Insuffisance Respiratoire aiguE (GRC-RESPIRE) Sorbonne Université, Sorbonne, France
| | - C Marois
- Sorbonne Université, AP-HP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, département de neurologie, unité de Médecine Intensive Réanimation à orientation neurologique, Paris, France
| | - S Demeret
- Sorbonne Université, AP-HP.Sorbonne Université, Hôpital de la Pitié-Salpêtrière, département de neurologie, unité de Médecine Intensive Réanimation à orientation neurologique, Paris, France
| | - E F M Wijdicks
- Mayo Clinic, Department of Neurology, 200 First Street SW, Rochester, MN 55905, USA
| | - N Weiss
- Groupe de Recherche Clinique en REanimation et Soins intensifs du Patient en Insuffisance Respiratoire aiguE (GRC-RESPIRE) Sorbonne Université, Sorbonne, France; Sorbonne Université, AP-HP, Sorbonne Université, Hôpital de la Pitié-Salpêtrière, département de neurologie, unité de Médecine Intensive Réanimation à orientation neurologique, Paris, France; Brain Liver Pitié-Salpêtrière (BLIPS) Study Group, INSERM UMR_S 938, Centre de recherche Saint-Antoine, Maladies métaboliques, biliaires et fibro-inflammatoire du foie, Institute of Cardiometabolism and Nutrition (ICAN), Paris, France.
| |
Collapse
|
|
20
|
Bertorini TE, Finder JD, Bassam BA. Perioperative Management of Patients With Neuromuscular Disorders. Neuromuscul Disord 2022. [DOI: 10.1016/b978-0-323-71317-7.00010-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
|
|
21
|
Ueno T, Toyama C, Deguchi K, Masahata K, Nomura M, Watanabe M, Kamiyama M, Tazuke Y, Bessho K, Okuyama H. Long-Term Outcome After Tacrolimus-Related Neurotoxicity in Pediatric Living Donor Liver Transplantation. Transplant Proc 2022; 54:468-471. [PMID: 35074159 DOI: 10.1016/j.transproceed.2021.12.036] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 12/29/2021] [Indexed: 01/14/2023]
|
|
22
|
Mousavi Ahmadian K, Serra Cabañas N, Cordoba Herrera C, Fayos de Arizon L, Perez Mir M, Guirado Perich L, Facundo Molas C. ssessment of Tacrolimus Neurotoxicity Measured by Retinal OCT. Transplant Proc 2021; 54:80-86. [PMID: 34911620 DOI: 10.1016/j.transproceed.2021.10.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 10/25/2021] [Indexed: 12/22/2022]
Abstract
BACKGROUND Neurotoxicity secondary to anticalcineurinics is a prevalent side effect in transplant recipients. Optical coherence tomography (OCT) scans the central nervous system by direct access to the retina. OCT assesses central nervous system involvement by measuring the thickness of the retinal layers, especially the ganglion cell layer (GCL). The retinal scan divides the scanned area into affected and unaffected segments, which can be quantified for each eye. The aim of this study was to determine retinal GCL thickness by means of OCT, analyzing the proportion of affected segments in individuals exposed to tacrolimus compared with a control group. MATERIALS AND METHODS We evaluated 20 renal transplant recipients exposed to tacrolimus for ≥6 months. The number of affected segments in the GCL of the retina was quantified by OCT. The control group was drawn from the general population attending routine ophthalmologic checkups. RESULTS Patients exposed to tacrolimus had a pathologic examination in 50% of cases compared with 20% in the control group (P < .044). Furthermore, among patients with an exposure time to tacrolimus >5 years, the examination was pathologic in 80% (P < .005). Linear regression analysis showed the presence of GCL segments with decreased thickness to be associated with the duration of exposure to tacrolimus (P = .036) and the time in dialysis before kidney transplant (P = .030). CONCLUSION Although this is a preliminary study, OCT scanning could serve to detect the neurotoxic effect of tacrolimus on the retinal GCL and central nervous system in renal transplant recipients.
Collapse
Affiliation(s)
- Kazem Mousavi Ahmadian
- Centre Ocular Quirúrgic de Terrassa, Terrassa, Spain; Servicio Oftalmología, Unidad de Retina, Hospital Universitari de Vic, Vic, Spain; Facultat de Medicina, Universitat de Vic - Universitat Central Catalunya, Vic, Spain
| | - Núria Serra Cabañas
- Servei Nefrologia, Fundació Puigvert, Barcelona, Spain; Servei Nefrologia Fundació Puigvert, Institutuo de Investigaciones Biomédicas Sant Pau (IIB-Sant Pau), Departamento de Medicina-Universitat Autònoma de Barcelona, REDin REN, Instituto de Investigación Carlos III, Barcelona, Spain
| | - Christian Cordoba Herrera
- Servei Nefrologia, Fundació Puigvert, Barcelona, Spain; Servei Nefrologia Fundació Puigvert, Institutuo de Investigaciones Biomédicas Sant Pau (IIB-Sant Pau), Departamento de Medicina-Universitat Autònoma de Barcelona, REDin REN, Instituto de Investigación Carlos III, Barcelona, Spain
| | - Leonor Fayos de Arizon
- Servei Nefrologia, Fundació Puigvert, Barcelona, Spain; Servei Nefrologia Fundació Puigvert, Institutuo de Investigaciones Biomédicas Sant Pau (IIB-Sant Pau), Departamento de Medicina-Universitat Autònoma de Barcelona, REDin REN, Instituto de Investigación Carlos III, Barcelona, Spain
| | - Mónica Perez Mir
- Centre Ocular Quirúrgic de Terrassa, Terrassa, Spain; Servicio Oftalmología, Unidad de Retina, Hospital Universitari de Vic, Vic, Spain; Facultat de Medicina, Universitat de Vic - Universitat Central Catalunya, Vic, Spain; Servei Nefrologia, Fundació Puigvert, Barcelona, Spain; Servei Nefrologia Fundació Puigvert, Institutuo de Investigaciones Biomédicas Sant Pau (IIB-Sant Pau), Departamento de Medicina-Universitat Autònoma de Barcelona, REDin REN, Instituto de Investigación Carlos III, Barcelona, Spain
| | - Lluís Guirado Perich
- Facultat de Medicina, Universitat de Vic - Universitat Central Catalunya, Vic, Spain; Servei Nefrologia, Fundació Puigvert, Barcelona, Spain; Servei Nefrologia Fundació Puigvert, Institutuo de Investigaciones Biomédicas Sant Pau (IIB-Sant Pau), Departamento de Medicina-Universitat Autònoma de Barcelona, REDin REN, Instituto de Investigación Carlos III, Barcelona, Spain
| | - Carme Facundo Molas
- Facultat de Medicina, Universitat de Vic - Universitat Central Catalunya, Vic, Spain.
| |
Collapse
|
|
23
|
Sato N, Marubashi S. Induction of Immune Tolerance in Islet Transplantation Using Apoptotic Donor Leukocytes. J Clin Med 2021; 10:5306. [PMID: 34830586 PMCID: PMC8625503 DOI: 10.3390/jcm10225306] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2021] [Revised: 10/31/2021] [Accepted: 11/10/2021] [Indexed: 11/17/2022] Open
Abstract
Allogeneic islet transplantation has become an effective treatment option for severe Type 1 diabetes with intractable impaired awareness due to hypoglycemic events. Although current immunosuppressive protocols effectively prevent the acute rejection associated with initial T cell activation in recipients, chronic rejection has remained an obstacle for achieving long-term allogeneic islet engraftment. The development of donor-specific immune tolerance to the allograft is the ultimate goal given its potential ability to overcome chronic rejection and disregard the need for maintenance immunosuppression, which may be toxic to islet grafts. Recently, a breakthrough in tolerance induction during allogeneic islet transplantation using apoptotic donor lymphocytes (ADLs) in a non-human primate model had been reported. Several studies have suggested that the clonal depletion, anergy, and expansion of the antigen-specific regulatory immune network are the mechanisms for donor-specific tolerance with ADLs, which act synergistically to induce robust transplant tolerance. This achievement represents a huge step forward toward the clinical application of immune tolerance induction. We herein summarize the reported operational induction therapies in islet transplantation using the ADLs. Moreover, a few obstacles for the engraftment of transplanted islets, such as islet immunogenicity and instant blood-mediated response, which need to be resolved in the future, are also discussed.
Collapse
Affiliation(s)
| | - Shigeru Marubashi
- Department of Hepato–Biliary–Pancreatic and Transplant Surgery, Fukushima Medical University, Hikagigaoka-1, Fukushima 960-1295, Japan;
| |
Collapse
|
|
24
|
Nogueira JM, Freire MJ, Nova VV, Jesus G. When Paranoia Comes with the Treatment: Psychosis Associated with Tacrolimus Use. Case Rep Nephrol Dial 2021; 11:241-246. [PMID: 34595211 PMCID: PMC8436620 DOI: 10.1159/000515048] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 01/29/2021] [Indexed: 11/19/2022] Open
Abstract
Tacrolimus is an immunosuppressive drug frequently used in solid organ transplant recipients. This drug has well-documented neuropsychiatric side effects in the literature, although emergence of psychotic symptoms is rare, being only described in a very few case reports. We present a case of a renal transplant recipient with no prior psychiatric history, who developed a severe psychosis secondary to supratherapeutic tacrolimus' blood concentrations. This case highlights the importance of clinical awareness to rare but severe neuropsychiatric effects due to tacrolimus use.
Collapse
Affiliation(s)
- João Machado Nogueira
- Department of Psychiatry and Mental Health, Centro Hospitalar de Setúbal, Setúbal, Portugal
| | - Maria João Freire
- Department of Psychiatry and Mental Health, Centro Hospitalar de Setúbal, Setúbal, Portugal
| | - Vanessa Vila Nova
- Department of Psychiatry and Mental Health, Centro Hospitalar de Setúbal, Setúbal, Portugal
| | - Gustavo Jesus
- Department of Liaison Psychiatry, Centro Hospitalar de Lisboa Central, Lisboa, Portugal.,Faculdade de Medicina de Lisboa, University Clinic of Psychiatry and Medical Psychology, Lisboa, Portugal
| |
Collapse
|
|
25
|
Ochoa-Sanchez R, Tamnanloo F, Rose CF. Hepatic Encephalopathy: From Metabolic to Neurodegenerative. Neurochem Res 2021; 46:2612-2625. [PMID: 34129161 DOI: 10.1007/s11064-021-03372-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Revised: 05/31/2021] [Accepted: 06/03/2021] [Indexed: 12/15/2022]
Abstract
Hepatic encephalopathy (HE) is a neuropsychiatric syndrome of both acute and chronic liver disease. As a metabolic disorder, HE is considered to be reversible and therefore is expected to resolve following the replacement of the diseased liver with a healthy liver. However, persisting neurological complications are observed in up to 47% of transplanted patients. Several retrospective studies have shown that patients with a history of HE, particularly overt-HE, had persistent neurological complications even after liver transplantation (LT). These enduring neurological conditions significantly affect patient's quality of life and continue to add to the economic burden of chronic liver disease on health care systems. This review discusses the journey of the brain through the progression of liver disease, entering the invasive surgical procedure of LT and the conditions associated with the post-transplant period. In particular, it will discuss the vulnerability of the HE brain to peri-operative factors and post-LT conditions which may explain non-resolved neurological impairment following LT. In addition, the review will provide evidence; (i) supporting overt-HE impacts on neurological complications post-LT; (ii) that overt-HE leads to permanent neuronal injury and (iii) the pathophysiological role of ammonia toxicity on astrocyte and neuronal injury/damage. Together, these findings will provide new insights on the underlying mechanisms leading to neurological complications post-LT.
Collapse
Affiliation(s)
- Rafael Ochoa-Sanchez
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, 900, rue Saint-Denis Pavillon R, R08.422, Montreal, QC, H2X-0A9, Canada
| | - Farzaneh Tamnanloo
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, 900, rue Saint-Denis Pavillon R, R08.422, Montreal, QC, H2X-0A9, Canada
| | - Christopher F Rose
- Hepato-Neuro Laboratory, CRCHUM, Université de Montréal, 900, rue Saint-Denis Pavillon R, R08.422, Montreal, QC, H2X-0A9, Canada.
| |
Collapse
|
|
26
|
Mulroy E, Baschieri F, Magrinelli F, Latorre A, Cortelli P, Bhatia KP. Movement Disorders and Liver Disease. Mov Disord Clin Pract 2021; 8:828-842. [PMID: 34401403 PMCID: PMC8354085 DOI: 10.1002/mdc3.13238] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 04/24/2021] [Accepted: 04/27/2021] [Indexed: 12/15/2022] Open
Abstract
The association of movement disorders with structural or functional hepatic disease occurs in three principal scenarios: (1) combined involvement of both organ systems from a single disease entity, (2) nervous system dysfunction resulting from exposure to toxic compounds in the setting of defective hepatic clearance, or (3) hepatic and/or neurological injury secondary to exposure to exogenous drugs or toxins. An important early step in the workup of any patient with combined movement disorders and liver disease is the exclusion of Wilson's disease. Diagnostic delay remains common for this treatable disorder, and this has major implications for patient outcomes. Thereafter, a structured approach integrating variables such as age of onset, tempo of progression, nature and severity of liver involvement, movement disorder phenomenology, exposure to drugs/toxins and laboratory/neuroimaging findings is key to ensuring timely diagnosis and disease‐specific therapy. Herein, we provide an overview of disorders which may manifest with a combination of movement disorders and liver disease, structured under the three headings as detailed above. In each section, the most common disorders are discussed, along with important clinical pearls, suggested diagnostic workup, differential diagnoses and where appropriate, treatment considerations.
Collapse
Affiliation(s)
- Eoin Mulroy
- Department of Clinical and Movement Neurosciences UCL Queen Square Institute of Neurology London United Kingdom
| | - Francesca Baschieri
- IRCCS Istituto delle Scienze Neurologiche di Bologna Bologna Italy.,Dipartimento di Scienze Biomediche e Neuromotorie Università di Bologna Bologna Italy
| | - Francesca Magrinelli
- Department of Clinical and Movement Neurosciences UCL Queen Square Institute of Neurology London United Kingdom.,Department of Neurosciences Biomedicine and Movement Sciences, University of Verona Verona Italy
| | - Anna Latorre
- Department of Clinical and Movement Neurosciences UCL Queen Square Institute of Neurology London United Kingdom
| | - Pietro Cortelli
- IRCCS Istituto delle Scienze Neurologiche di Bologna Bologna Italy.,Dipartimento di Scienze Biomediche e Neuromotorie Università di Bologna Bologna Italy
| | - Kailash P Bhatia
- Department of Clinical and Movement Neurosciences UCL Queen Square Institute of Neurology London United Kingdom
| |
Collapse
|
|
27
|
Wang Z, Zhao M, Gao S. Epileptic Seizures After Allogeneic Hematopoietic Stem Cell Transplantation. Front Neurol 2021; 12:675756. [PMID: 34335446 PMCID: PMC8322618 DOI: 10.3389/fneur.2021.675756] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Accepted: 06/17/2021] [Indexed: 12/02/2022] Open
Abstract
Technique in allogeneic hematopoietic stem cell transplantation has greatly advanced over the past decades, which has led to an increase in the number of patients receiving transplantation, but the complex procedure places these transplant recipients at high risk of a large spectrum of complications including neurologic involvement. As a common manifestation of neurological disorders, epileptic seizures after transplantation have been of great concern to clinicians because it seriously affects the survival rate and living quality of those recipients. The aim of this review is to elucidate the incidence of seizures after allogeneic hematopoietic stem cell transplantation, and to further summarize in detail its etiologies, possible mechanisms, clinical manifestations, therapeutic schedule, and prognosis, hoping to improve doctors' understandings of concurrent seizures following transplantation, so they can prevent, process, and eventually improve the survival and outlook for patients in a timely manner and correctly.
Collapse
Affiliation(s)
- Zhuo Wang
- Department of Hematology, The First Hospital of Jilin University, Changchun, China
| | - Munan Zhao
- Department of Oncology, The First Hospital of Jilin University, Changchun, China
| | - Sujun Gao
- Department of Hematology, The First Hospital of Jilin University, Changchun, China
| |
Collapse
|
|
28
|
Mansourabadi AH, Mohamed Khosroshahi L, Noorbakhsh F, Amirzargar A. Cell therapy in transplantation: A comprehensive review of the current applications of cell therapy in transplant patients with the focus on Tregs, CAR Tregs, and Mesenchymal stem cells. Int Immunopharmacol 2021; 97:107669. [PMID: 33965760 DOI: 10.1016/j.intimp.2021.107669] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 04/06/2021] [Accepted: 04/07/2021] [Indexed: 02/07/2023]
Abstract
Organ transplantation is a practical treatment for patients with end-stage organ failure. Despite the advances in short-term graft survival, long-term graft survival remains the main challenge considering the increased mortality and morbidity associated with chronic rejection and the toxicity of immunosuppressive drugs. Since a novel therapeutic strategy to induce allograft tolerance seems urgent, focusing on developing novel and safe approaches to prolong graft survival is one of the main goals of transplant investigators. Researchers in the field of organ transplantation are interested in suppressing or optimizing the immune responses by focusing on immune cells including mesenchymal stem cells (MSCs), polyclonal regulatory Tcells (Tregs), and antigen-specific Tregs engineered with chimeric antigen receptors (CAR Tregs). We review the mechanistic pathways, phenotypic and functional characteristics of these cells, and their promising application in organ transplantation.
Collapse
Affiliation(s)
- Amir Hossein Mansourabadi
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, 009821 Tehran, Iran; Network of Immunity in Infection, Malignancy, and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), 009821 Tehran, Iran; Systematic Review and Meta-Analysis Expert Group (SRMEG), Universal Scientific Education and Research Network (USERN), 009821 Tehran, Iran
| | - Leila Mohamed Khosroshahi
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, 009821 Tehran, Iran
| | - Farshid Noorbakhsh
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, 009821 Tehran, Iran.
| | - Aliakbar Amirzargar
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, 009821 Tehran, Iran.
| |
Collapse
|
|
29
|
Kanamori K, Kubota M, Sakamoto S, Ishiguro A, Kasahara M. Neurological complications after living-donor liver transplantation in children. Brain Dev 2021; 43:637-643. [PMID: 33546953 DOI: 10.1016/j.braindev.2021.01.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Revised: 01/07/2021] [Accepted: 01/19/2021] [Indexed: 12/19/2022]
Abstract
AIM Liver transplantation (LT) has been used as a definitive management for children with end-stage liver disease or acute liver failure. Living-donor LT (LDLT) has been a common type of LT performed in Asian countries, including Japan, where deceased donors are rarely available. However, the neurological complications (NCs) associated with LDLT remain unknown. The purpose of this study was to clarify the characteristics of NCs in children after LDLT. METHODS This study is a retrospective observational study carried out at a tertiary children's hospital in Japan. We studied children who had undergone LDLT between January 2001 and January 2020. RESULTS We examined 602 cases of LT, of which 559 were LDLT cases (92.9%). NCs after LT were present in 21 cases (3.8%). The most common neurological symptoms were seizure (n = 17), whereas disturbance of consciousness without seizure was observed in four cases. The frequency of NCs for each of the indications was 12.2% for fulminant hepatic failure, 6.5% for metabolic liver disease, and 0.7% for cholestatic liver disease. INTERPRETATION We report the characteristics of NCs after LDLT in children. The frequency of NCs after LT was high in cases of fulminant hepatic failure and metabolic diseases, who might have had neurological symptoms or impaired consciousness before LT.
Collapse
Affiliation(s)
- Keita Kanamori
- Center for Postgraduate Education and Training, National Center for Child Health and Development, Tokyo, Japan.
| | - Masaya Kubota
- Division of Neurology, National Center for Child Health and Development, Tokyo, Japan
| | - Seisuke Sakamoto
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Akira Ishiguro
- Center for Postgraduate Education and Training, National Center for Child Health and Development, Tokyo, Japan
| | - Mureo Kasahara
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| |
Collapse
|
|
30
|
Functional Improvement of Tacrolimus-Induced Parkinsonism With Amantadine After Liver Transplantation: A Case Report. Clin Neuropharmacol 2021; 44:141-144. [PMID: 33871425 DOI: 10.1097/wnf.0000000000000444] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
ABSTRACT Drug-induced parkinsonism is the most common type of drug-induced movement disorder, whose symptoms can decrease patient quality of life and reduce medication compliance. Tacrolimus is a routinely used immunosuppressant agent after liver transplantation, with a well-known neurotoxic profile. There have been rare reports of tacrolimus-induced parkinsonism, but its pharmacologic management and functional impact remain poorly characterized in the literature. We present a case of tacrolimus-induced parkinsonism in a 62-year-old man after a liver transplant, resulting in significant neurologic impairments and multiple barriers to hospital discharge. His tremor, rigidity, bradykinesia, gait dysfunction, dysphonia, and dysphagia significantly improved after starting low-dose amantadine, with increased functional independence that allowed for a safe discharge. This is the first case in the literature detailing tacrolimus-induced parkinsonism's functional impairments improving with amantadine monotherapy.
Collapse
|
|
31
|
Abstract
Tacrolimus was discovered in 1984 and entered clinical use shortly thereafter, contributing to successful solid organ transplantation across the globe. In this review, we cover development of tacrolimus, its evolving clinical utility, and issues affecting its current usage. Since earliest use of this class of immunosuppressant, concerns for calcineurin-inhibitor toxicity have led to efforts to minimize or eliminate these agents in clinical regimens but with limited success. Current understanding of the role of tacrolimus focuses more on its efficacy in preventing graft rejection and graft loss. As we enter the fourth decade of tacrolimus use, newer studies utilizing novel combinations (as with the mammalian target of rapamycin inhibitor, everolimus, and T-cell costimulation blockade with belatacept) offer potential for enhanced benefits.
Collapse
Affiliation(s)
- Song C Ong
- Department of Medicine, Division of Nephrology, University of Alabama at Birmingham, Birmingham, AL
| | - Robert S Gaston
- Department of Medicine, Division of Nephrology, University of Alabama at Birmingham, Birmingham, AL
- CTI Clinical Trial and Consulting, Inc., Covington, KT
| |
Collapse
|
|
32
|
Celikkan FT, Hayirli Ozyol N, Nakkas H, Evirgen O. Ultrastructural and morphometric alterations to the peripheral nerve following the administration of immunosuppressive agent tacrolimus (FK506). Ultrastruct Pathol 2021; 45:112-117. [PMID: 33596749 DOI: 10.1080/01913123.2021.1881673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Tacrolimus, a widely used immunosuppressive drug for preventing graft rejection following organ transplantation, was reported to develop neurotoxic side effects ranging from mild to severe symptoms in the literature. Rats were randomly divided into three groups as control and 2-week and 3-week treatment groups and received a 2 mg/kg/day tacrolimus by oral gavage. Animals were sacrificed and sciatic nerves obtained from all groups were fixed and processed for light and electron microscopic investigations. The myelinated fiber diameter, axon diameter, G-ratio (axon diameter/myelinated fiber diameter), and myelin thickness were also determined. The data obtained in the control and tacrolimus-treated groups were compared.The control group sciatic nerve fascicles showed normal morphology with myelinated and unmyelinated fibers. Experimental groups exhibited axonal dilatation, irregularly thickened and vacuolated myelin sheaths with separation of myelin layers. The morphometric analysis showed that the myelinated fibers of the 2-week tacrolimus-treated group displayed a moderate increase in the myelin thickness and axon and fiber diameter in comparison with the control and 3-week tacrolimus-treated groups. The G-ratio was found to be in normal range in all groups and there were no statistically significant difference.The present study indicates that the treatment with tacrolimus may produce a mild degenerative change but prolonged drug administration for 3 weeks led to improvement in morphometric and morphologic data and the normal G-ratio values, suggesting that the regeneration capacity of the myelinated fibers maintains their normal function to transmit nerve impulses.
Collapse
Affiliation(s)
- Ferda Topal Celikkan
- Faculty of Medicine, Department of Histology and Embryology, Ankara University, Ankara, Turkey
| | - Nazli Hayirli Ozyol
- Faculty of Medicine, Department of Histology and Embryology, Hitit University, Corum, Turkey
| | - Hilal Nakkas
- Faculty of Medicine, Department of Histology and Embryology, Ankara Yildirim Beyazit University, Ankara, Turkey
| | - Oya Evirgen
- Faculty of Medicine, Department of Histology and Embryology, Ankara University, Ankara, Turkey
| |
Collapse
|
|
33
|
Han EX, Wang J, Kural M, Jiang B, Leiby KL, Chowdhury N, Tellides G, Kibbey RG, Lawson JH, Niklason LE. Development of a Bioartificial Vascular Pancreas. J Tissue Eng 2021; 12:20417314211027714. [PMID: 34262686 PMCID: PMC8243137 DOI: 10.1177/20417314211027714] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Accepted: 06/08/2021] [Indexed: 12/16/2022] Open
Abstract
Transplantation of pancreatic islets has been shown to be effective, in some patients, for the long-term treatment of type 1 diabetes. However, transplantation of islets into either the portal vein or the subcutaneous space can be limited by insufficient oxygen transfer, leading to islet loss. Furthermore, oxygen diffusion limitations can be magnified when islet numbers are increased dramatically, as in translating from rodent studies to human-scale treatments. To address these limitations, an islet transplantation approach using an acellular vascular graft as a vascular scaffold has been developed, termed the BioVascular Pancreas (BVP). To create the BVP, islets are seeded as an outer coating on the surface of an acellular vascular graft, using fibrin as a hydrogel carrier. The BVP can then be anastomosed as an arterial (or arteriovenous) graft, which allows fully oxygenated arterial blood with a pO2 of roughly 100 mmHg to flow through the graft lumen and thereby supply oxygen to the islets. In silico simulations and in vitro bioreactor experiments show that the BVP design provides adequate survivability for islets and helps avoid islet hypoxia. When implanted as end-to-end abdominal aorta grafts in nude rats, BVPs were able to restore near-normoglycemia durably for 90 days and developed robust microvascular infiltration from the host. Furthermore, pilot implantations in pigs were performed, which demonstrated the scalability of the technology. Given the potential benefits provided by the BVP, this tissue design may eventually serve as a solution for transplantation of pancreatic islets to treat or cure type 1 diabetes.
Collapse
Affiliation(s)
- Edward X Han
- Department of Biomedical Engineering,
Yale School of Engineering and Applied Science, New Haven, CT, USA
| | - Juan Wang
- Vascular Biology and Therapeutics
Program, Yale School of Medicine, New Haven, CT, USA
- Department of Anesthesiology, Yale
School of Medicine, New Haven, CT, USA
| | - Mehmet Kural
- Vascular Biology and Therapeutics
Program, Yale School of Medicine, New Haven, CT, USA
- Department of Anesthesiology, Yale
School of Medicine, New Haven, CT, USA
| | - Bo Jiang
- Department of Surgery, Yale School of
Medicine, New Haven, CT, USA
- Department of Vascular Surgery, The
First Hospital of China Medical University, Shenyang, China
| | - Katherine L Leiby
- Department of Biomedical Engineering,
Yale School of Engineering and Applied Science, New Haven, CT, USA
| | - Nazar Chowdhury
- Molecular, Cellular, and Developmental
Biology, Yale University, New Haven, CT, USA
| | - George Tellides
- Vascular Biology and Therapeutics
Program, Yale School of Medicine, New Haven, CT, USA
- Department of Surgery, Yale School of
Medicine, New Haven, CT, USA
- Veterans Affairs Connecticut Healthcare
System, West Haven, CT, USA
| | - Richard G Kibbey
- Department of Internal Medicine
(Endocrinology), Yale University, New Haven, CT, USA
- Department of Cellular & Molecular
Physiology, Yale School of Medicine, New Haven, CT, USA
| | - Jeffrey H Lawson
- Department of Surgery, Duke
University, Durham, NC, USA
- Humacyte Inc., Durham, NC, USA
| | - Laura E Niklason
- Department of Biomedical Engineering,
Yale School of Engineering and Applied Science, New Haven, CT, USA
- Vascular Biology and Therapeutics
Program, Yale School of Medicine, New Haven, CT, USA
- Department of Anesthesiology, Yale
School of Medicine, New Haven, CT, USA
- Humacyte Inc., Durham, NC, USA
| |
Collapse
|
|
34
|
Maximova N, Marcuzzi A, Del Rizzo I, Zanon D, Maestro A, Barbi E, Sala R. Standard treatment-refractory cytomegalovirus encephalitis unmasked by immune reconstitution inflammatory syndrome and successfully treated with virus-specific hyperimmune globulin. Clin Transl Immunology 2020; 9:e1201. [PMID: 33235734 PMCID: PMC7670254 DOI: 10.1002/cti2.1201] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 09/23/2020] [Accepted: 10/02/2020] [Indexed: 01/21/2023] Open
Abstract
Objectives Cytomegalovirus (CMV)‐related encephalitis is a rare but potentially life‐threatening complication of CMV infection in immunocompromised patients. The high mortality rate is associated with deficient immune system reconstitution after hematopoietic stem cell transplant (HSCT) and poor bioavailability of antiviral drugs in cerebrospinal fluid (CSF). CMV‐related central nervous system (CNS) infection may occur with aspecific symptoms, without evidence of either blood viral load or magnetic resonance imaging (MRI) signs of encephalitis. Methods Here, we describe a 10‐year‐old girl who underwent an allogeneic HSCT and subsequently developed CMV encephalitis. Because of the absence of CMV antigen in the blood, the diagnosis of encephalitis was proposed only after a delay, following the onset of immune reconstitution inflammatory syndrome (IRIS). Two months of combined dual antiviral therapy with ganciclovir and foscarnet proved ineffective against CMV and caused significant bone marrow and renal toxicity. To avoid further toxicity, the girl was given daily treatment with CMV‐hyperimmune globulins alone. Results After three weeks, the CSF viral load dropped significantly and was undetectable within three more weeks. In the meantime, the renal impairment resolved, and there was a complete bone marrow recovery. Conclusion We suggest that this patient succeeded in achieving CMV CSF clearance with high dose of CMV‐hyperimmune globulin, given alone, because of the ability of immunoglobulins to penetrate the blood–brain barrier (BBB).
Collapse
Affiliation(s)
- Natalia Maximova
- Institute for Maternal and Child Health - IRCCS Burlo Garofolo Trieste Italy
| | | | | | - Davide Zanon
- Institute for Maternal and Child Health - IRCCS Burlo Garofolo Trieste Italy
| | - Alessandra Maestro
- Institute for Maternal and Child Health - IRCCS Burlo Garofolo Trieste Italy
| | - Egidio Barbi
- Institute for Maternal and Child Health - IRCCS Burlo Garofolo Trieste Italy.,University of Trieste Trieste Italy
| | | |
Collapse
|
|
35
|
Mesripour A, Golbidi M, Hajhashemi V. Dextromethorphan improved cyclosporine-induced depression in mice model of despair. Res Pharm Sci 2020; 15:447-453. [PMID: 33628286 PMCID: PMC7879785 DOI: 10.4103/1735-5362.297847] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Revised: 04/22/2020] [Accepted: 09/23/2020] [Indexed: 12/28/2022] Open
Abstract
Background and purpose: Cyclosporine (Cyc) is a calcineurin inhibitor used in immunosuppressive therapy that may cause psychological problems such as depression. Previous investigations have shown the positive antidepressant effects of dextromethorphan (Dxt). Therefore, the aim of this study was the evaluation of the Dxt effect on Cyc-induced depression in an animal model of despair in two separate cohorts. Experimental approach: Male albino mice were used, first total activity was evaluated by the locomotor test, and then after that, the immobility time during the forced swimming test was measured as an indicator of depression. Cyc, Dxt, and fluoxetine (the reference antidepressant drug) were all administered IP. Tests were performed either 4 h after injection (cohort 4 h) or in separate groups 24 h after injection (cohort 24 h). Findings/Results: Cyc reduced total activity measured after 4 h in the locomotor test and it was normalized after 24 h. Immobility time dose-dependently increased during the forced swimming test and remained so after 24 h (cohort 24 h; Cyc 10, 20, and 40 mg/kg, 157 ± 22, 180 ± 8, and 228 ± 4 s, respectively; Cyc 40 mg/kg P < 0.001 vs control 142 ± 13 s) that indicated Cyc induced depressive-like behavior. Dxt (30 mg/kg) like fluoxetine reduced the immobility time when co-administered with Cyc compared with Cyc and remained effective after 24 h (cohort 24 h; 120 ± 30, P < 0.001 vs Cyc 40 mg/kg alone). Conclusion and implications: Dxt was a useful drug for preventing Cyc-induced depression that remained effective for 24 h in mice. Since interpretation from animal studies to humans must be done with caution further clinical studies on the effect of Dxt in patients suffering from psychological side effects of Cyc may be reasonable.
Collapse
Affiliation(s)
- Azadeh Mesripour
- Department of Pharmacology and Toxicology, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, I.R. Iran
| | - Mojgan Golbidi
- Department of Pharmacology and Toxicology, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, I.R. Iran
| | - Valiollah Hajhashemi
- Department of Pharmacology and Toxicology, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, I.R. Iran.,Isfahan Pharmaceutical Sciences Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, I.R. Iran
| |
Collapse
|
|
36
|
Coe CL, Horst SN, Izzy MJ. Neurologic Toxicities Associated with Tumor Necrosis Factor Inhibitors and Calcineurin Inhibitors. Neurol Clin 2020; 38:937-951. [PMID: 33040870 DOI: 10.1016/j.ncl.2020.07.009] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The calcineurin inhibitors cyclosporine and tacrolimus are used for their immunosuppressive effects. Neurotoxic side effects include tremor, paresthesia, and headache. Rarer neurotoxicities include seizure, posterior reversible encephalopathy syndrome, and encephalopathy. Tacrolimus tends to be more neurotoxic than cyclosporine. Management of toxicities associated with calcineurin inhibitors includes dose reduction, switching between calcineurin inhibitors, or switching to a calcineurin-free regimen. Tumor necrosis factor (TNF) inhibitors are used in autoimmune diseases. Management of demyelinating conditions among patients treated with anti-TNF should follow standard of care and withdrawal of the anti-TNF. This drug class should be avoided in patients with a history of demyelinating conditions.
Collapse
Affiliation(s)
- Christopher L Coe
- Department of Medicine, Section of Hospital Medicine, Vanderbilt University Medical Center, 1161 21st Avenue South, Nashville, TN 37232, USA. https://twitter.com/ccoemd
| | - Sarah N Horst
- Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, 1211 21st Avenue South, Medical Arts Building, Suite 220, Nashville, TN 37232, USA. https://twitter.com/HorstIBDDoc
| | - Manhal J Izzy
- Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Transplant Hepatology, 1660 The Vanderbilt Clinic, Nashville, TN 37232, USA.
| |
Collapse
|
|
37
|
Peak blood pressure and prediction of posterior reversible encephalopathy syndrome in children. Pediatr Nephrol 2020; 35:1967-1975. [PMID: 32385528 PMCID: PMC8086820 DOI: 10.1007/s00467-020-04577-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Revised: 04/06/2020] [Accepted: 04/15/2020] [Indexed: 10/24/2022]
Abstract
BACKGROUND Hypertension is a risk factor for posterior reversible encephalopathy syndrome (PRES), but the timing and severity of hypertension relative to PRES are unknown. The objective was to identify a clinically meaningful blood pressure (BP) threshold that predicts PRES development in high-risk children. METHODS We recorded peak systolic BP, diastolic BP, BP z-scores, and mean arterial pressure over the 14 days preceding clinical concern for PRES in 35 subjects who developed PRES, compared to 14 controls who had normal brain magnetic resonance imaging and similar underlying disease, renal function, and medications. We used multivariable logistic regression models adjusted for fluid overload and obesity to estimate the association of peak BP with PRES. We used receiver operating characteristic curves to determine which peak BP thresholds best predicted PRES and calculated the corresponding sensitivity, specificity, and positive and negative predictive values. RESULTS Peak systolic BP z-score was most strongly associated with PRES (OR 3.97, 95% CI 1.62-9.74), and peak systolic BP z-score ≥ 3.0 predicted PRES (area under the curve 0.95, 95% CI 0.88-1.0) with 91% sensitivity and 85% specificity, indicating 94% positive predictive value and 79% negative predictive value. CONCLUSIONS We demonstrated that peak systolic BP z-score ≥ 3.0 in the preceding 14 days predicted PRES development in cases compared with controls in children at high risk. Our study suggests that stage 2 hypertension, corresponding to a z-score ≥ 3.0, could help define hypertensive emergency in high-risk children and indicate when more aggressive treatment is warranted to prevent neurologic injury.
Collapse
|
|
38
|
Executive Functioning in Pediatric Solid Organ Transplant Recipients: A Meta-analytic Review. Transplantation 2020; 104:357-366. [PMID: 31517786 DOI: 10.1097/tp.0000000000002954] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
BACKGROUND Examining executive functioning (EF) posttransplant has become increasingly prevalent, as EF deficits are associated with poor disease-related outcomes and psychosocial functioning. The purpose of the current meta-analysis was to compare overall and domain-specific EF between healthy youth and those with a kidney, heart, or liver transplant, and identify moderating variables related to EF differences between these 2 groups. METHODS A literature search of PsycINFO, Pubmed, and Medline was conducted for eligible articles published until January 2019. Twenty studies met eligibility criteria and were included in the present meta-analysis. RESULTS Results from the random-effects model indicated a significant standardized mean difference in overall EF skills with transplant recipients demonstrating worse EF (g = 0.40; 95% confidence interval [CI], 0.29-0.50) than healthy youth. Specifically, transplanted youth had worse working memory (g = 0.33; 95% CI, 0.01-0.66), processing speed (g = 0.41; 95% CI, 0.19-0.62), attentional control (g = 0.53; 95% CI, 0.33-0.73), and metacognitive skills (g = 0.36; 95% CI, 0.18-0.54). Assessment type and time since transplantation were not significant moderators. CONCLUSIONS Pediatric solid organ transplant recipients demonstrate worse overall EF skills and deficits in working memory, processing speed, attentional control, and metacognitive skills. Many children who have undergone solid organ transplantation will require additional support in medical and academic settings because of deficits in various EF domains.
Collapse
|
|
39
|
Sagou K, Fukushima N, Ukai S, Goto M, Ozeki K, Kohno A. Intrapatient variability in concentration/dose ratio of tacrolimus predicts transplant-associated thrombotic microangiopathy. Int J Hematol 2020; 113:63-72. [PMID: 32876853 DOI: 10.1007/s12185-020-02986-8] [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: 07/11/2020] [Revised: 08/20/2020] [Accepted: 08/25/2020] [Indexed: 10/23/2022]
Abstract
Tacrolimus (TAC) is essential for prophylaxis of acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic cell transplantation (allo-HSCT). We have sometimes observed large fluctuations in TAC concentration. However, links between the variability in the concentration or the concentration/dose (C/D) ratio of TAC and clinical complications remain ambiguous. To clarify relationships between various parameters of TAC and early complications such as pre-engraftment immune reactions/engraftment syndrome, aGVHD, and transplant-associated thrombotic microangiopathy (TA-TMA), a total of 146 patients who underwent allo-HSCT were included. Intrapatient variabilities in the concentration and C/D ratio of TAC were estimated by intrapatient mean absolute deviation (iMAD). The mean concentration and C/D ratio of TAC were not significantly different between with and without complications. A strong association was observed between greater iMAD for TAC C/D ratio from days 15 to 21 and the development of TA-TMA. iMAD values for TAC C/D ratio of 11.4 or greater was a risk factor for TA-TMA and the cumulative incidence of nonrelapse mortality (NRM) was significantly higher in patients with iMAD values for TAC C/D ratio of 11.4 or greater. Intrapatient variability in the C/D ratio of TAC was associated with the incidence of TA-TMA and NRM and might be useful for predicting TA-TMA.
Collapse
Affiliation(s)
- Ken Sagou
- Department of Hematology and Oncology, JA Aichi Konan Kosei Hospital, 137, Omatsubara, Takaya-cho, Konan, Aichi, 483-8704, Japan. .,Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan.
| | - Nobuaki Fukushima
- Department of Hematology and Oncology, JA Aichi Konan Kosei Hospital, 137, Omatsubara, Takaya-cho, Konan, Aichi, 483-8704, Japan
| | - Shun Ukai
- Department of Hematology and Oncology, JA Aichi Konan Kosei Hospital, 137, Omatsubara, Takaya-cho, Konan, Aichi, 483-8704, Japan
| | - Miyo Goto
- Department of Hematology and Oncology, JA Aichi Konan Kosei Hospital, 137, Omatsubara, Takaya-cho, Konan, Aichi, 483-8704, Japan
| | - Kazutaka Ozeki
- Department of Hematology and Oncology, JA Aichi Konan Kosei Hospital, 137, Omatsubara, Takaya-cho, Konan, Aichi, 483-8704, Japan
| | - Akio Kohno
- Department of Hematology and Oncology, JA Aichi Konan Kosei Hospital, 137, Omatsubara, Takaya-cho, Konan, Aichi, 483-8704, Japan
| |
Collapse
|
|
40
|
Meena P, Bhargava V, Rana D, Bhalla A, Gupta A. An Approach to Neurological Disorders in a Kidney Transplant Recipient. KIDNEY360 2020; 1:837-844. [PMID: 35372958 DOI: 10.34067/kid.0002052020] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Accepted: 06/11/2020] [Indexed: 11/27/2022]
Abstract
Kidney transplantation is the preferred treatment modality in patients with ESKD. However, there are associated complications that arise from immunosuppressive medications, infections, and associated comorbidities. Neurologic disorders frequently develop in patients who have received a kidney transplant, which in turn increases the associated morbidity and mortality. This review discusses the common neurologic disorders after kidney transplantation, including infections, cognitive decline, drug-related conditions, malignancy, seizure, and other neurologic complications.
Collapse
|
|
41
|
Liu JF, Shen T, Zhang YT. Posterior reversible encephalopathy syndrome and heart failure tacrolimus-induced after liver transplantation: A case report. World J Clin Cases 2020; 8:2870-2875. [PMID: 32742997 PMCID: PMC7360704 DOI: 10.12998/wjcc.v8.i13.2870] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Revised: 05/07/2020] [Accepted: 06/13/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Patients undergoing liver transplantation can develop posterior reversible encephalopathy syndrome (PRES) and acute heart failure (HF) in the post-operative period. But PRES with HF caused by tacrolimus has rarely been described.
CASE SUMMAR A 40-year-old female patient who had a normal preoperative cardiac and neural evaluation developed PRES with acute heart failure tacrolimus-induced after liver transplantation. The challenges associated with both diagnosis and management in the setting of a newly implanted graft are discussed.
CONCLUSION Tacrolimus can induce neurotoxicity and then cardiac toxicity. Magnetic resonance imaging, echocardiography, and increased brain natriuretic peptide may be predictive of post-operative PRES with acute heart failure. Further investigations are necessary to verify this finding.
Collapse
Affiliation(s)
- Jun-Fang Liu
- Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Tian Shen
- Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| | - Yun-Tao Zhang
- Division of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
| |
Collapse
|
|
42
|
Teimouri A, Ahmadi SR, Anavri Ardakani S, Foroughian M. Cyclosporine-A-Based Immunosuppressive Therapy-Induced Neurotoxicity: A Case Report. Open Access Emerg Med 2020; 12:93-97. [PMID: 32431553 PMCID: PMC7197938 DOI: 10.2147/oaem.s241501] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2019] [Accepted: 04/18/2020] [Indexed: 11/23/2022] Open
Abstract
Cyclosporine-A (CsA) and mycophenolate mofetil are immunosuppressive drugs used for the prevention of transplant rejection. Various clinical studies have been performed on different forms of CsA neurotoxicity, including tremor, paresthesia, confusion, ataxia, neuralgia, hemiplegia, occipital seizures, and transient cortical blindness. Mycophenolate is associated with several neurological side effects including headache, insomnia, dizziness, depression, confusion, hypertonia, and paresthesia. A 31-year-old male with a history of kidney transplantation was treated with CsA and mycophenolate mofetil, for 18 years. He had been referred to the emergency department with complaints of generalized tonic-clonic seizure for 1 minute and 15 minutes of the post-ictal phase. Almost all laboratory tests including cerebrospinal fluid analysis were within normal limits. Brain MRI findings were compatible with CsA-based neurotoxicity. The patient's symptoms and MRI findings improved on decreasing CsA to the minimum dose. CsA neurotoxicity is more common in intravenous therapy, early days of CsA administration, P450 inhibitors administration, and following liver transplantation. MRI findings in CsA neurotoxicity include signal changes in the cerebral cortex and juxtacortical white matter of the occipital lobes, temporal, parietal, and frontal lobes. Every year, many solid organ transplantations are performed. Many of these patients received CsA-based regimens for the prevention of rejection. Therefore, it is necessary to consider CsA neurotoxicity in suspected patients.
Collapse
Affiliation(s)
- Ali Teimouri
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Sayyed Reza Ahmadi
- Department of Emergency Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Mahdi Foroughian
- Department of Emergency Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| |
Collapse
|
|
43
|
Diffusion MRI Findings in Encephalopathy Induced by Immunosuppressive Therapy after Liver Transplantation. Case Rep Med 2020; 2020:1015385. [PMID: 32110241 PMCID: PMC7042546 DOI: 10.1155/2020/1015385] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Revised: 01/10/2020] [Accepted: 01/20/2020] [Indexed: 11/18/2022] Open
Abstract
Neurological complications are common after liver transplantation, as they affect up to one-third of the transplanted patients and are associated with significant morbidity. The introduction of calcineurin inhibitors, cyclosporine A and tacrolimus, in immunosuppressive regimens significantly improved the outcome of solid-organ transplantation even though immunosuppression-associated neurotoxicity remains a significant complication, particularly occurring in about 25% of cases after liver transplantation. The immunosuppressant cyclosporine A and tacrolimus have been associated with the occurrence of major neurological complications, diffuse encephalopathy being the most common. The biochemical and pathogenetic basis of calcineurin inhibitors-induced neurotoxicity are still unclear although several mechanisms have been suggested. Early recognition of symptoms could help reduce neurotoxic event. The aim of the study was to evaluate cerebral changes through MRI, in particular with diffusion-weighted images (DWI) and apparent diffusion coefficient (ADC) maps, in two patients undergoing liver transplantation after immunosuppressive therapy. We describe two patients in which clinical pictures, presenting as a severe neurological condition, early after orthotopic liver transplantation during immunosuppression therapy, showed a different evolution in keeping with evidence of focal-multifocal lesions at DWI and ADC maps. At clinical onset, DWI showed hyperintensity of the temporo-parieto-occipital cortex with normal ADC values in the patient with following good clinical recovery and decreased values in the other one; in the latter case, MRI abnormalities were still present after ten days, until the patient's exitus. The changes in DWI with normal ADC may be linked to brain edema with a predominant vasogenic component and therefore reversible, while the reduction in ADC is due to cytotoxic edema and linked to more severe, nonreversible, clinical picture. Brain MRI and particularly DWI and ADC maps provide not only a good and early representation of neurological complications during immunosuppressant therapy but can also provide a useful prognostic tool on clinical outcome of the patient.
Collapse
|
|
44
|
Farouk SS, Rein JL. The Many Faces of Calcineurin Inhibitor Toxicity-What the FK? Adv Chronic Kidney Dis 2020; 27:56-66. [PMID: 32147003 DOI: 10.1053/j.ackd.2019.08.006] [Citation(s) in RCA: 130] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Accepted: 08/01/2019] [Indexed: 02/07/2023]
Abstract
Calcineurin inhibitors (CNIs) are both the savior and Achilles' heel of kidney transplantation. Although CNIs have significantly reduced rates of acute rejection, their numerous toxicities can plague kidney transplant recipients. By 10 years, virtually all allografts will have evidence of CNI nephrotoxicity. CNIs have been strongly associated with hypertension, dyslipidemia, and new onset of diabetes after transplantation-significantly contributing to cardiovascular risk in the kidney transplant recipient. Multiple electrolyte derangements including hyperkalemia, hypomagnesemia, hypercalciuria, metabolic acidosis, and hyperuricemia may be challenging to manage for the clinician. Finally, CNI-associated tremor, gingival hyperplasia, and defects in hair growth can have a significant impact on the transplant recipient's quality of life. In this review, the authors briefly discuss the pharmacokinetics of CNI and discuss the numerous clinically relevant toxicities of commonly used CNIs, cyclosporine and tacrolimus.
Collapse
|
|
45
|
Sirenko O, Parham F, Dea S, Sodhi N, Biesmans S, Mora-Castilla S, Ryan K, Behl M, Chandy G, Crittenden C, Vargas-Hurlston S, Guicherit O, Gordon R, Zanella F, Carromeu C. Functional and Mechanistic Neurotoxicity Profiling Using Human iPSC-Derived Neural 3D Cultures. Toxicol Sci 2019; 167:58-76. [PMID: 30169818 DOI: 10.1093/toxsci/kfy218] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
Neurological disorders affect millions of people worldwide and appear to be on the rise. Whereas the reason for this increase remains unknown, environmental factors are a suspected contributor. Hence, there is an urgent need to develop more complex, biologically relevant, and predictive in vitro assays to screen larger sets of compounds with the potential for neurotoxicity. Here, we employed a human induced pluripotent stem cell (iPSC)-based 3D neural platform composed of mature cortical neurons and astrocytes as a model for this purpose. The iPSC-derived human 3D cortical neuron/astrocyte co-cultures (3D neural cultures) present spontaneous synchronized, readily detectable calcium oscillations. This advanced neural platform was optimized for high-throughput screening in 384-well plates and displays highly consistent, functional performance across different wells and plates. Characterization of oscillation profiles in 3D neural cultures was performed through multi-parametric analysis that included the calcium oscillation rate and peak width, amplitude, and waveform irregularities. Cellular and mitochondrial toxicity were assessed by high-content imaging. For assay characterization, we used a set of neuromodulators with known mechanisms of action. We then explored the neurotoxic profile of a library of 87 compounds that included pharmaceutical drugs, pesticides, flame retardants, and other chemicals. Our results demonstrated that 57% of the tested compounds exhibited effects in the assay. The compounds were then ranked according to their effective concentrations based on in vitro activity. Our results show that a human iPSC-derived 3D neural culture assay platform is a promising biologically relevant tool to assess the neurotoxic potential of drugs and environmental toxicants.
Collapse
Affiliation(s)
| | - Frederick Parham
- Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina
| | - Steven Dea
- StemoniX, Inc, Maple Grove, Minnesota 55311
| | - Neha Sodhi
- StemoniX, Inc, Maple Grove, Minnesota 55311
| | | | | | - Kristen Ryan
- Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina
| | - Mamta Behl
- Division of the National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina
| | | | | | | | | | | | | | | |
Collapse
|
|
46
|
Saffari TM, Bedar M, Zuidam JM, Shin AY, Baan CC, Hesselink DA, Hundepool CA. Exploring the neuroregenerative potential of tacrolimus. Expert Rev Clin Pharmacol 2019; 12:1047-1057. [DOI: 10.1080/17512433.2019.1675507] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- T. M. Saffari
- Department of Plastic-, Reconstructive- and Hand Surgery, Erasmus Medical Center, Rotterdam, The Netherlands
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
| | - M. Bedar
- Department of Plastic-, Reconstructive- and Hand Surgery, Erasmus Medical Center, Rotterdam, The Netherlands
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
| | - J. M. Zuidam
- Department of Plastic-, Reconstructive- and Hand Surgery, Erasmus Medical Center, Rotterdam, The Netherlands
| | - A. Y. Shin
- Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN, USA
| | - C. C. Baan
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, The Netherlands
| | - D. A. Hesselink
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, The Netherlands
| | - C. A. Hundepool
- Department of Plastic-, Reconstructive- and Hand Surgery, Erasmus Medical Center, Rotterdam, The Netherlands
| |
Collapse
|
|
47
|
Cajanding R. Immunosuppression following organ transplantation. Part 2: complications and their management. ACTA ACUST UNITED AC 2019; 27:1059-1065. [PMID: 30281349 DOI: 10.12968/bjon.2018.27.18.1059] [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: 12/12/2022]
Abstract
Advances in the care of patients who have had a solid organ transplant has led to a growing population of post-transplant patients, who are also living for longer. As a result of their longer life expectancy, transplant recipients often face a multitude of challenges, including optimising their immunosuppressive regimens and managing potential complications. Life-threatening infections, malignancies, and organ-specific toxicities are the complications post-transplant patients commonly encounter and these complications are often associated with increased morbidity and mortality, adverse graft functioning and survival, profound impairment in the patient's quality of life, and significant healthcare burden. This article, the second of two parts, gives an overview of the issues involved in the care of patients who are receiving immunosuppressants. The common complications encountered by post-transplant patients are discussed and their assessment, management, prevention and treatment explored.
Collapse
Affiliation(s)
- Ruff Cajanding
- Staff Nurse, Liver Intensive Therapy Unit, Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London
| |
Collapse
|
|
48
|
Importance of Hematopoietic Mixed Chimerism for Induction of Renal Allograft Tolerance in Nonhuman Primates. Transplantation 2019; 103:689-697. [PMID: 30300283 DOI: 10.1097/tp.0000000000002470] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
BACKGROUND Although induction of durable mixed chimerism is required for murine skin allograft tolerance (TOL), renal allograft TOL has been achieved after induction of only transient mixed chimerism in nonhuman primates (NHPs) and humans. To better define the level/duration of chimerism required for stable renal allograft TOL, we retrospectively analyzed these parameters and compared them with transplant outcomes in NHP combined kidney and bone marrow transplant recipients. METHODS Peripheral blood levels and duration of myeloid or lymphoid chimerism were retrospectively analyzed in 34 NHP combined kidney and bone marrow transplantation recipients which were divided into 3 groups: TOL, n = 10; chronic antibody-mediated rejection (CAMR), n = 12; and T cell-mediated rejection (TCMR), n = 12. RESULTS All 4 of the recipients that failed to develop any chimerism lost their allografts due to TCMR after discontinuation of immunosuppression (56 ± 3 d). Among 30 recipients who successfully developed multilineage chimerism, 10 achieved long-term immunosuppression-free survival without rejection (1258 ± 388 d), 12 eventually developed CAMR (932 ± 155 d), and 8 developed TCMR (82 ± 10 d). The maximum level but not duration of lymphoid chimerism was significantly higher in TOL recipients compared with both CAMR (P = 0.0159) and TCMR (P = 0.0074). On the other hand, the maximum myeloid chimerism was significantly higher in TOL than in TCMR (P = 0.0469), but not in CAMR. Receiver operating characteristic analyses revealed that lymphoid chimerism levels of 3.1% or greater could reliably predict long-term immunosuppression-free renal allograft survival (P < 0.0001). CONCLUSIONS This retrospective study confirmed that induction of chimerism is essential for long-term immunosuppression-free survival, which best correlates with lymphoid chimerism levels higher than 3.1%.
Collapse
|
|
49
|
Recent Topics on The Mechanisms of Immunosuppressive Therapy-Related Neurotoxicities. Int J Mol Sci 2019; 20:ijms20133210. [PMID: 31261959 PMCID: PMC6651704 DOI: 10.3390/ijms20133210] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Revised: 06/26/2019] [Accepted: 06/28/2019] [Indexed: 02/07/2023] Open
Abstract
Although transplantation procedures have been developed for patients with end-stage hepatic insufficiency or other diseases, allograft rejection still threatens patient health and lifespan. Over the last few decades, the emergence of immunosuppressive agents such as calcineurin inhibitors (CNIs) and mammalian target of rapamycin (mTOR) inhibitors have strikingly increased graft survival. Unfortunately, immunosuppressive agent-related neurotoxicity commonly occurs in clinical practice, with the majority of neurotoxicity cases caused by CNIs. The possible mechanisms through which CNIs cause neurotoxicity include increasing the permeability or injury of the blood–brain barrier, alterations of mitochondrial function, and alterations in the electrophysiological state. Other immunosuppressants can also induce neuropsychiatric complications. For example, mTOR inhibitors induce seizures, mycophenolate mofetil induces depression and headaches, methotrexate affects the central nervous system, the mouse monoclonal immunoglobulin G2 antibody (used against the cluster of differentiation 3) also induces headaches, and patients using corticosteroids usually experience cognitive alteration. Therapeutic drug monitoring, individual therapy based on pharmacogenetics, and early recognition of symptoms help reduce neurotoxic events considerably. Once neurotoxicity occurs, a reduction in the drug dosage, switching to other immunosuppressants, combination therapy with drugs used to treat the neuropsychiatric manifestation, or blood purification therapy have proven to be effective against neurotoxicity. In this review, we summarize recent topics on the mechanisms of immunosuppressive drug-related neurotoxicity. In addition, information about the neuroprotective effects of several immunosuppressants is also discussed.
Collapse
|
|
50
|
daCruz K, Cousino MK, Smith T, Bilhartz J, Eder SJ, Fredericks EM. Educational needs in families of pediatric liver and kidney transplant recipients: A quality improvement project. Pediatr Transplant 2019; 23:e13412. [PMID: 30983080 DOI: 10.1111/petr.13412] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Revised: 01/07/2019] [Accepted: 03/08/2019] [Indexed: 11/28/2022]
Abstract
Parents of pediatric liver and kidney transplant recipients were surveyed regarding their current education plans (eg, Individualized Education Program, 504), satisfaction with these plans, and interest in educational support from the psychosocial transplant team. Survey results indicate high rates of IEP and 504 plans, academic and related services, and accommodations among this population. The majority of parents/guardians reported satisfaction with their child's current school plan and did not report need for additional transplant team support specific to school services on the survey measure. However, other information highlights the importance for pediatric transplant teams to consider other ways to support this population's educational needs.
Collapse
Affiliation(s)
- Katelin daCruz
- Department of Pediatrics, University of Michigan, Ann Arbor, Michigan
| | - Melissa K Cousino
- Department of Pediatrics, University of Michigan, Ann Arbor, Michigan
| | - Tanya Smith
- Department of Social Work, C.S. Mott Children's Hospital, Ann Arbor, Michigan
| | - Jacob Bilhartz
- Department of Pediatrics, University of Michigan, Ann Arbor, Michigan
| | - Sally J Eder
- Department of Pediatrics, University of Michigan, Ann Arbor, Michigan
| | | |
Collapse
|