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Tai CJ, Huang KH, Wang JY, Gau SY, Huang SW, Su KY, Tsai TH, Wu CN, Lee CY. Risk of Incident Post-Transplantation Diabetes Mellitus After Solid Organ Transplantation in Taiwan: A Population-Based Cohort Study. Healthcare (Basel) 2025; 13:523. [PMID: 40077085 PMCID: PMC11898666 DOI: 10.3390/healthcare13050523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Revised: 02/20/2025] [Accepted: 02/26/2025] [Indexed: 03/14/2025] Open
Abstract
Background: Solid organ transplant (SOT) recipients have an elevated risk of diabetes mellitus (DM). This study investigated the risk of posttransplant DM (PTDM) in a retrospective cohort study. Methods: We analyzed patients aged over 18 years who received an SOT between 2002 and 2013. Each patient was matched with four control individuals by age, sex, insured salary, urbanization level, Charlson's comorbidity index (CCI), and year of inclusion in the study. After matching, the study comprised 6874 patients who underwent an SOT and 27,496 matched general patients as the comparison. The risk of DM among the SOT recipients was assessed using a Cox proportional hazards model after adjustment for all relevant variables. Results: The SOT cohort had a significantly higher risk of DM than general patients (adjusted hazard ratio [aHR], 1.61; 95% confidence interval [CI], 1.51-1.72). Kidney and liver recipients, respectively, had DM incidence rates 1.57 (95% CI, 1.46-1.70) and 1.73 (95% CI, 1.53-1.94) times that of the general patients. Conclusions: SOT recipients had an elevated risk of DM. Among various organ recipients, liver recipients had the highest PTDM risk. Kidney and liver recipients demonstrated the highest DM risk at 6 months after their SOT. The risk of PTDM following an SOT may result in long-term consequences. Hence, we advise the critical need for proper management to mitigate related complications after transplantation.
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Affiliation(s)
- Chih-Jaan Tai
- Department of Otorhinolaryngology-Head and Neck Surgery, China Medical University Hospital, Taichung 404327, Taiwan;
- School of Medicine, China Medical University, Taichung 404328, Taiwan
| | - Kuang-Hua Huang
- Department of Health Services Administration, China Medical University, Taichung 406040, Taiwan; (K.-H.H.); (T.-H.T.)
| | - Jiun-Yi Wang
- Department of Healthcare Administration, Asia University, Taichung 413305, Taiwan;
- Department of Medical Research, China Medical University Hospital, Taichung 404327, Taiwan
| | - Shuo-Yan Gau
- School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan; (S.-Y.G.); (S.-W.H.); (K.-Y.S.)
- Department of Business Administration, National Taiwan University, Taipei 106319, Taiwan
| | - Shiang-Wen Huang
- School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan; (S.-Y.G.); (S.-W.H.); (K.-Y.S.)
| | - Kun-Yu Su
- School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan; (S.-Y.G.); (S.-W.H.); (K.-Y.S.)
| | - Tung-Han Tsai
- Department of Health Services Administration, China Medical University, Taichung 406040, Taiwan; (K.-H.H.); (T.-H.T.)
| | - Chun-Nan Wu
- Department of Pharmacology, Chung Shan Medical University, Taichung 40201, Taiwan
- Department of Pharmacy, Chung Shan Medical University Hospital, Taichung 40201, Taiwan
| | - Chien-Ying Lee
- Department of Pharmacology, Chung Shan Medical University, Taichung 40201, Taiwan
- Department of Pharmacy, Chung Shan Medical University Hospital, Taichung 40201, Taiwan
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McBee MK, Butani L. Post-transplant diarrhea in pediatric kidney transplant recipients. Pediatr Nephrol 2025:10.1007/s00467-024-06572-6. [PMID: 39907757 DOI: 10.1007/s00467-024-06572-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 10/02/2024] [Accepted: 10/03/2024] [Indexed: 02/06/2025]
Abstract
Diarrhea is a common complication after pediatric kidney transplantation. While mycophenolate mofetil is an important and common cause of post-transplant diarrhea, diarrhea can result from infectious and other non-infectious causes. Many complications can result from severe diarrhea including acute kidney injury from dehydration. Other unique complications in transplant recipients include tacrolimus toxicity and acute rejection (from changes in immunosuppressive pharmacokinetics or dosing in response to the diarrhea). Therefore, a thorough evaluation is recommended for all pediatric patients with severe diarrhea to ensure that appropriate interventions are instituted, and risks of complications minimized. Our review describes the scope of the morbidity of diarrheal illness after transplantation, common causes, and newer insights in the management of diarrhea, both supportive and targeted to the underlying cause.
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Affiliation(s)
- Machi Kaneko McBee
- Division of Pediatric Nephrology, Department of Pediatrics, University of California, Davis, 2516 Stockton Blvd, Sacramento, CA, 95817, USA.
| | - Lavjay Butani
- Division of Pediatric Nephrology, Department of Pediatrics, University of California, Davis, 2516 Stockton Blvd, Sacramento, CA, 95817, USA
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Fong KY, Lim EJ, So WZ, Aslim EJ, Tiong HY, Gan VHL. Management of bladder cancer in kidney transplant recipients: A narrative review. Bladder Cancer 2025; 11:23523735251321986. [PMID: 40034246 PMCID: PMC11863735 DOI: 10.1177/23523735251321986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Accepted: 01/28/2025] [Indexed: 03/05/2025]
Abstract
Background Bladder cancer in the setting of previous a kidney transplant (KT) is challenging to manage due to complex medical and surgical considerations. Objective To provide a comprehensive evaluation of the scope of management of bladder cancer in KT patients, and describe the controversies surrounding these management options. Methods A systematic review of studies reporting management of KT patients with bladder cancer and involving ≥3 patients was performed. A narrative review was also performed for various aspects of management such as pathophysiology, surgical considerations, intravesical therapy, immunosuppression and oncological surveillance. Results Bladder cancer incidence in KT recipients is 2.8-4.1 times higher than the general population, and there is a notable association with aristolochic acid nephropathy as well as BK virus oncogenesis. Regarding surgical treatment, transurethral resection is preferred for non-muscle invasive tumors, and intravesical BCG for intermediate- and high-risk patients appears to be underutilized despite its safety and associated reduction in recurrence. Radical cystectomy with limited pelvic lymph node dissection, urinary diversion, and consideration of bilateral nephroureterectomy appears to be the safest method of oncological control in muscle-invasive tumors. A switch in immunosuppressive regimens to mTOR inhibitors may be considered in lieu of its antitumor effects. Routine surveillance in KT patients with risk factors for bladder cancer is challenging and may be warranted especially in the Asian population which has a higher rate of urothelial malignancy. Conclusions This review provides a thorough summary of management strategies for bladder cancer in the setting of previous KT.
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Affiliation(s)
- Khi Yung Fong
- Department of Surgery, Singapore General Hospital, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Ee Jean Lim
- Department of Urology, Singapore General Hospital, Singapore
| | - Wei Zheng So
- Department of Urology, National University Hospital, Singapore
| | | | - Ho Yee Tiong
- Department of Urology, National University Hospital, Singapore
- National University Centre for Organ Transplantation, Singapore
| | - Valerie Huei Li Gan
- Department of Urology, Singapore General Hospital, Singapore
- SingHealth Duke-NUS Transplant Centre, Singapore
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Dash K, Mishra M. The tradeoff between the efficacy of calcineurin inhibitors: prevention of allograft rejection vs. post-transplant renal and cardiovascular complications. Crit Rev Toxicol 2025; 55:63-79. [PMID: 39807635 DOI: 10.1080/10408444.2024.2433631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Accepted: 11/19/2024] [Indexed: 01/16/2025]
Abstract
Solid organ transplantation has emerged as a crucial intervention in the field of medicine. During transplantation, our human body perceives the organ as an exogenous entity or graft, initiating an immune reaction to eliminate it. This immune response ultimately culminates in the rejection of the graft. So, to mitigate the possibility of graft rejection, implementing immune suppression is imperative. In this context, the utilization of calcineurin inhibitors (CNIs) assumes a pivotal role. Calcineurin inhibitors significantly preserve immunosuppression following solid organ transplantation. Calcineurin inhibitors have considerably improved short-term results in renal transplantation by reducing acute rejection rates. Concerning the limited therapeutic window of these medications, careful monitoring of pharmacological treatment and individual doses is required. However, a significant number of patients do experience CNI toxicity. Side effects of CNIs include renal failure, hypertension, respiratory disorders, gastrointestinal damage, gingivitis, and so on. Higher trough level of the drug causes acute nephrotoxicity, which is of three types: functional toxicity, tubular toxicity, and vascular toxicity. Acute nephrotoxicity, if untreated, leads to irreversible, progressive deterioration of allograft function, leading to chronic nephrotoxicity. Cardiovascular toxicity of CNIs includes atrial hypertension caused by vasoconstriction of the afferent arteriole, vascular remodeling, hypertrophy, dyslipidemia, and also the onset of diabetes. Such clinical complications further affect the patient's survivability and subjective well-being, possibly leading to graft loss. This review focuses on the most severe side effects of CNIs: renal and cardiovascular toxicity.
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Affiliation(s)
- Kalpanarani Dash
- Department of Life Sciences, Neural Developmental Biology Lab, National Institute of Technology, Rourkela, India
| | - Monalisa Mishra
- Department of Life Sciences, Neural Developmental Biology Lab, National Institute of Technology, Rourkela, India
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Suilik HA, Al-Shammari AS, Soliman Y, Suilik MA, Naeim KA, Nawlo A, Abuelazm M. Efficacy of tacrolimus versus cyclosporine after lung transplantation: an updated systematic review, meta-analysis, and trial sequential analysis of randomized controlled trials. Eur J Clin Pharmacol 2024; 80:1923-1935. [PMID: 39261378 DOI: 10.1007/s00228-024-03750-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Accepted: 08/26/2024] [Indexed: 09/13/2024]
Abstract
BACKGROUND Little data supports using tacrolimus versus cyclosporin for immunosuppression concerning acute rejection and bronchiolitis obliterans syndrome/Chronic Lung Allograft Dysfunction CLAD complications following lung transplantation (LTx). Our goal was to evaluate the use of tacrolimus versus cyclosporine in preventing these complications after LTx. METHODS We included randomized controlled trials (RCTs) by searching PubMed, Web of Science, SCOPUS, and Cochrane through January 10th, 2024. We pooled dichotomous data using the risk ratio (RR) and continuous data using the mean difference (MD) with a 95% confidence interval (CI). RESULTS We included Four RCTs with a total of 677 patients. Tacrolimus was significantly associated with decreased risk of acute rejection (RR: 1.21, 95% CI [1.03, 1.42], I2 = 25%, P = 0.02) compared with cyclosporine, bronchiolitis obliterans syndrome/CLAD (RR: 1.87, 95% CI [1.26, 2.77], I2 = 52%, P = 0.002), and treatment withdrawal (RR: 3.11, 95% CI [2.06, 4.70], I2 = 0%, P = < 0.00001). However, tacrolimus significantly increased the risk of new-onset diabetes (RR: 0.33, 95% CI [0.12, 0.91], I2 = 0%, P = 0.03), and kidney dysfunction (RR: 0.79, 95% CI [0.66, 0.93], I2 = 0%, P = 0.006). In contrast, there was no difference in the incidence of all-cause mortality (RR: 91, 95% CI [0.68, 1.22], I2 = 0%, P = 0.53), arterial hypertension (RR: 2.40, 95% CI [0.41, 14.21], I2 = 92%, P = 0.33), and new cancer (RR: 1.57, 95% CI [0.79, 3.10], I2 = 4%, P = 0.20). CONCLUSION Tacrolimus has decreased acute rejection episodes and CLAD rate than cyclosporine, but it increased the risk of new-onset diabetes and kidney dysfunction.
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Affiliation(s)
| | | | | | | | | | - Ahmad Nawlo
- Department of Infectious Disease, Brigham and Women's Hospital, Harvard Medical School, Boston, USA
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Wong ETY, Pochinco D, Vathsala A, Koh WK, Lim A, Sran HK, D’Costa MR, Chang ZY, Nickerson PW, Wiebe C. HLA-DR/DQ eplet mismatch predicts de novo donor-specific antibody development in multi-ethnic Southeast Asian kidney transplant recipients on different immunosuppression regimens. Front Genet 2024; 15:1447141. [PMID: 39262421 PMCID: PMC11387181 DOI: 10.3389/fgene.2024.1447141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 08/14/2024] [Indexed: 09/13/2024] Open
Abstract
Eplet mismatch has been recognized as a more precise strategy for determining HLA compatibility by analyzing donor-recipient HLA differences at the molecular level. However, predicting post-transplant alloimmunity using single-molecule eplet mismatch categories has not been validated in Asian cohorts. We examined a cohort of Southeast Asian kidney transplant recipients (n = 234) to evaluate HLA-DR/DQ eplet mismatch as a predictor of de novo donor-specific antibody (dnDSA) development. HLA-DR/DQ single-molecule eplet mismatch was quantified using HLA Matchmaker, and we utilized previously published HLA-DR/DQ eplet mismatch thresholds to categorize recipients into alloimmune risk groups and evaluate their association with dnDSA development. Recognizing that the predominance of cyclosporine use (71%) may alter published eplet mismatch thresholds derived from a largely tacrolimus-based (87%) cohort, we evaluated cohort-specific thresholds for HLA-DR/DQ single-molecule eplet mismatch categories. Recipient ethnicities included Chinese (65%), Malays (17%), Indians (14%), and others (4%). HLA-DR/DQ dnDSA developed in 29/234 (12%) recipients after a median follow-up of 5.4 years, including against isolated HLA-DR (n = 7), isolated HLA-DQ (n = 11), or both (n = 11). HLA-DR/DQ single-molecule eplet mismatch risk categories correlated with dnDSA-free survival (p = 0.001) with low-risk recipients having a dnDSA prevalence of 1% over 5 years. The cohort-specific alloimmune risk categories improved correlation with HLA-DR/DQ dnDSA-free survival and remained significant after adjusting for calcineurin inhibitor and anti-metabolite immunosuppression (p < 0.001). We validated the performance of single-molecule eplet mismatch categories as a prognostic biomarker for HLA-DR/DQ dnDSA development in a cohort of predominantly Asian kidney transplant recipients after adjusting for different immunosuppression regimens.
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Affiliation(s)
- Emmett Tsz Yeung Wong
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- National University Centre for Organ Transplantation, National University Hospital, Singapore, Singapore
- Department of Medicine, University of Manitoba, Winnipeg, MB, Canada
| | | | - Anantharaman Vathsala
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- National University Centre for Organ Transplantation, National University Hospital, Singapore, Singapore
| | - Wee Kun Koh
- National University Centre for Organ Transplantation, National University Hospital, Singapore, Singapore
| | - Amy Lim
- National University Centre for Organ Transplantation, National University Hospital, Singapore, Singapore
| | - Hersharan Kaur Sran
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- National University Centre for Organ Transplantation, National University Hospital, Singapore, Singapore
| | - Matthew Ross D’Costa
- National University Centre for Organ Transplantation, National University Hospital, Singapore, Singapore
| | - Zi Yun Chang
- National University Centre for Organ Transplantation, National University Hospital, Singapore, Singapore
| | - Peter W. Nickerson
- Department of Medicine, University of Manitoba, Winnipeg, MB, Canada
- Shared Health Services Manitoba, Winnipeg, MB, Canada
- Department of Immunology, University of Manitoba, Winnipeg, MB, Canada
| | - Chris Wiebe
- Department of Medicine, University of Manitoba, Winnipeg, MB, Canada
- Shared Health Services Manitoba, Winnipeg, MB, Canada
- Department of Immunology, University of Manitoba, Winnipeg, MB, Canada
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Udomkarnjananun S, Schagen MR, Hesselink DA. A review of landmark studies on maintenance immunosuppressive regimens in kidney transplantation. ASIAN BIOMED 2024; 18:92-108. [PMID: 39175954 PMCID: PMC11338012 DOI: 10.2478/abm-2024-0015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/24/2024]
Abstract
Immunosuppressive medications play a pivotal role in kidney transplantation, and the calcineurin inhibitors (CNIs), including cyclosporine A (CsA) and tacrolimus (TAC), are considered as the backbone of maintenance immunosuppressive regimens. Since the introduction of CNIs in kidney transplantation, the incidence of acute rejection has decreased, and allograft survival has improved significantly. However, CNI nephrotoxicity has been a major concern, believed to heavily impact long-term allograft survival and function. To address this concern, several CNI-sparing regimens were developed and studied in randomized, controlled, clinical trials, aiming to reduce CNI exposure and preserve long-term allograft function. However, more recent information has revealed that CNI nephrotoxicity is not the primary cause of late allograft failure, and its histopathology is neither specific nor pathognomonic. In this review, we discuss the historical development of maintenance immunosuppressive regimens in kidney transplantation, covering the early era of transplantation, the CNI-sparing era, and the current era where the alloimmune response, rather than CNI nephrotoxicity, appears to be the major contributor to late allograft failure. Our goal is to provide a chronological overview of the development of maintenance immunosuppressive regimens and summarize the most recent information for clinicians caring for kidney transplant recipients (KTRs).
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Affiliation(s)
- Suwasin Udomkarnjananun
- Division of Nephrology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok10330, Thailand
- Excellence Center for Solid Organ Transplantation, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok10330, Thailand
- Renal Immunology and Transplantation Research Unit, Faculty of Medicine, Chulalongkorn University, Bangkok10330, Thailand
- Center of Excellence on Translational Research in Inflammation and Immunology (CETRII), Department of Microbiology, Chulalongkorn University, Bangkok10330, Thailand
| | - Maaike R. Schagen
- Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam3000, The Netherlands
| | - Dennis A. Hesselink
- Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam3000, The Netherlands
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Mohib O, Vanderhulst J, Catalano C, Roussoulières A, Knoop C, Lemoine A, Baudoux T. Variables Associated With Hyperkalemic Renal Tubular Acidosis in Solid Organ Transplant Recipients. Cureus 2024; 16:e55379. [PMID: 38434606 PMCID: PMC10908377 DOI: 10.7759/cureus.55379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/02/2024] [Indexed: 03/05/2024] Open
Abstract
INTRODUCTION The occurrence of hyperkalemic renal tubular acidosis (RTA) in the post-transplantation period is likely underestimated, and its identification remains important to offer adequate medical management. Transplant recipients frequently present with clinical and biological characteristics that may be associated with the occurrence of this complication. METHODS This was a single-center retrospective study that compared transplanted patients with hyperkalemic RTA and a control group to identify variables associated with the occurrence of this complication. Fisher's exact test and the Mann-Whitney test, followed by multivariate logistic regression, were applied to test whether there was a significant association between hyperkalemic RTA and different variables. RESULTS Kidney and heart transplant recipients were at greater risk of developing RTA than lung transplant recipients (p = 0.016). There was also a significant association between the development of RTA and kalemia (p < 0.01), chloremia (p < 0.01), and bicarbonatemia (p < 0.01). The significant impact of these last three variables was confirmed by the results of the multivariate logistic regression. Residual serum tacrolimus levels (p = 0.13) and creatinine levels (p = 0.17) of renal transplant patients were not significantly associated with hyperkalemic RTA. CONCLUSION The type of transplanted organ, kalemia, chloremia, and bicarbonatemia were significantly associated with the occurrence of hyperkalemic RTA. This study calls into question certain approaches to managing this complication proposed in a number of case reports, such as reducing the target serum residual of tacrolimus or discontinuing trimethoprim-sulfamethoxazole (TMP-SMX) in favor of another antibiotic prophylactic agent, potentially exposing patients to graft rejection and opportunistic infections.
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Affiliation(s)
- Othmane Mohib
- Department of Nephrology, Cliniques Universitaires de Bruxelles - Hôpital (CUB) Erasme, Brussels, BEL
| | - Julien Vanderhulst
- Internal Medicine, Centre Hospitalier Universitaire (CHU) Brugmann, Brussels, BEL
| | - Concetta Catalano
- Department of Nephrology, Cliniques Universitaires de Bruxelles - Hôpital (CUB) Erasme, Brussels, BEL
| | - Ana Roussoulières
- Department of Cardiology, Cliniques Universitaires de Bruxelles - Hôpital (CUB) Erasme, Brussels, BEL
| | - Christiane Knoop
- Department of Pulmonology, Cliniques Universitaires de Bruxelles - Hôpital (CUB) Erasme, Brussels, BEL
| | - Alain Lemoine
- Department of Nephrology, Cliniques Universitaires de Bruxelles - Hôpital (CUB) Erasme, Brussels, BEL
| | - Thomas Baudoux
- Department of Nephrology, Cliniques Universitaires de Bruxelles - Hôpital (CUB) Erasme, Brussels, BEL
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Ratviset P, Panombualert S, Chathum K, Wisanuyotin S. Outcomes of pediatric deceased donor kidney transplant in northeast Thailand. Pediatr Transplant 2024; 28:e14411. [PMID: 37294688 DOI: 10.1111/petr.14411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 08/27/2022] [Accepted: 09/30/2022] [Indexed: 06/11/2023]
Abstract
BACKGROUND Kidney transplantation (KT) is the best therapy in children with end-stage renal disease (ESRD), however, improving long-term graft survival remains challenging. The aim of this study was to determine graft survival and potential risk factors in pediatric patients who undergo deceased donor KT with a steroid-based regimen. METHODS The medical records of children who underwent their first deceased donor KT in Srinagarind Hospital (Khon Kaen, Thailand) between 2001 and 2020 were reviewed. RESULTS Seventy-two patients were studied. Male adolescents were the predominant recipients and the majority of donors were young adult males. Non-glomerular disease, particularly hypoplastic/dysplastic kidney disease, was the major cause of ESRD (48.61%). The mean cold ischemic time (CIT) was 18.29 ± 5.29 h. Most of the recipients had more than 4 human leukocyte antigen (HLA) mismatched loci with positive HLA-DR mismatch (52.78%). Induction therapy was administered in 76.74% of recipients. Tacrolimus plus mycophenolate sodium and prednisolone was the most common immunosuppressive maintenance regimen (69.44%). Graft failure occurred in 18 patients, mostly due to graft rejection (50%). Graft survival at 1, 3, and 5 years after KT were 94.40%, 86.25%, and 74.92%, respectively. The only significant risk factor of graft failure in this study was delayed graft function (DGF) (adjusted HR = 3.55; 95%CI: 1.14, 11.12; p = .029). Patient survival at 1, 3, and 5 years was 100%, 98.48%, and 96.19%, respectively. CONCLUSION The short-term outcomes of pediatric KT from deceased donors were satisfactory; however, prevention of DGF would result in better outcomes.
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Affiliation(s)
- Preeyapat Ratviset
- Department of Pediatrics, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Sunee Panombualert
- Department of Pediatrics, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Kannika Chathum
- Outpatient Department, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Suwannee Wisanuyotin
- Department of Pediatrics, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
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Veitch M, Beaumont K, Pouwer R, Chew HY, Frazer IH, Soyer HP, Campbell S, Dymock BW, Harvey A, Cock TA, Wells JW. Local blockade of tacrolimus promotes T-cell-mediated tumor regression in systemically immunosuppressed hosts. J Immunother Cancer 2023; 11:e006783. [PMID: 37678918 PMCID: PMC10496666 DOI: 10.1136/jitc-2023-006783] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/30/2023] [Indexed: 09/09/2023] Open
Abstract
BACKGROUND Immunosuppressive drugs such as tacrolimus have revolutionized our ability to transplant organs between individuals. Tacrolimus acts systemically to suppress the activity of T-cells within and around transplanted organs. However, tacrolimus also suppresses T-cell function in the skin, contributing to a high incidence of skin cancer and associated mortality and morbidity in solid organ transplant recipients. Here, we aimed to identify a compound capable of re-establishing antitumor T-cell control in the skin despite the presence of tacrolimus. METHODS In this study, we performed time-resolved fluorescence resonance energy transfer to identify molecules capable of antagonizing the interaction between tacrolimus and FKBP12. The capacity of these molecules to rescue mouse and human T-cell function in the presence of tacrolimus was determined in vitro, and the antitumor effect of the lead compound, Q-2361, was assessed in "regressor" models of skin cancer in immunosuppressed mice. Systemic CD8 T-cell depletion and analyses of intratumoral T-cell activation markers and effector molecule production were performed to determine the mechanism of tumor rejection. Pharmacokinetic studies of topically applied Q-2361 were performed to assess skin and systemic drug exposure. RESULTS Q-2361 potently blocked the interaction between tacrolimus and FKBP12 and reversed the inhibition of the nuclear factor of activated T cells activation by tacrolimus following T-cell receptor engagement in human Jurkat cells. Q-2361 rescued T-cell function in the presence of tacrolimus, rapamycin, and everolimus. Intratumoral injection of Q-2361-induced tumor regression in mice systemically immune suppressed with tacrolimus. Mechanistically, Q-2361 treatment permitted T-cell activation, proliferation, and effector function within tumors. When CD8 T cells were depleted, Q-2361 could not induce tumor regression. A simple solution-based Q-2361 topical formulation achieved high and sustained residence in the skin with negligible drug in the blood. CONCLUSIONS Our findings demonstrate that the local application of Q-2361 permits T-cells to become activated driving tumor rejection in the presence of tacrolimus. The data presented here suggests that topically applied Q-2361 has great potential for the reactivation of T-cells in the skin but not systemically, and therefore represents a promising strategy to prevent or treat skin malignancies in immunosuppressed organ transplant recipients.
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Affiliation(s)
- Margaret Veitch
- Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - Kimberly Beaumont
- Queensland Emory Drug Discovery Initiative, UniQuest, The University of Queensland, Brisbane, Queensland, Australia
| | - Rebecca Pouwer
- Queensland Emory Drug Discovery Initiative, UniQuest, The University of Queensland, Brisbane, Queensland, Australia
| | - Hui Yi Chew
- Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - Ian H Frazer
- Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - H Peter Soyer
- Frazer Institute, Dermatology Research Centre, The University of Queensland, Brisbane, Queensland, Australia
- Department of Dermatology, Princess Alexandra Hospital, Brisbane, Queensland, Australia
| | - Scott Campbell
- Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
- Department of Nephrology, Princess Alexandra Hospital, Brisbane, Queensland, Australia
| | - Brian W Dymock
- Queensland Emory Drug Discovery Initiative, UniQuest, The University of Queensland, Brisbane, Queensland, Australia
| | - Andrew Harvey
- Queensland Emory Drug Discovery Initiative, UniQuest, The University of Queensland, Brisbane, Queensland, Australia
| | - Terrie-Anne Cock
- Queensland Emory Drug Discovery Initiative, UniQuest, The University of Queensland, Brisbane, Queensland, Australia
| | - James W Wells
- Frazer Institute, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
- Frazer Institute, Dermatology Research Centre, The University of Queensland, Brisbane, Queensland, Australia
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11
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Bacle A, Lhermitte R, Le Daré B, Mercerolle M, Vigneau C, Le Corre P, Chemouny JM. Unexpected overdose of oral cyclosporine in a kidney transplant patient: a case report. Eur J Hosp Pharm 2023; 30:242-244. [PMID: 34117088 PMCID: PMC10359783 DOI: 10.1136/ejhpharm-2021-002730] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Accepted: 06/01/2021] [Indexed: 11/04/2022] Open
Abstract
Cyclosporine is a widely used immunosuppressive agent to prevent rejection of solid organ transplant. Here, we describe the case of a 71-year-old man who received the prescribed dose of cyclosporine 10 times 6 days after a kidney transplantation because of a concentration miscalculation involving two galenic forms. The patient presented gastrointestinal and neurological disorders. Therapeutic drug monitoring revealed high cyclosporine blood concentrations (693 ng/mL, therapeutic range 100-300 ng/mL). Symptomatic management of digestive disorders was performed, and haemodialysis was started the day after the cyclosporine overdose in the face of acute renal failure. The patient's disorders were quickly resolved. The dosing regimen was adapted in order to administer the most appropriate galenic form and to avoid another administration error. Long-term follow-up showed no failure of renal transplantation. The purpose of this case report is to warn physicians and clinical pharmacists about the vigilance required on cyclosporine prescription, especially when two galenic forms are administered to obtain the prescribed dose.
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Affiliation(s)
- Astrid Bacle
- Pôle Pharmacie, Service Hospitalo-Universitaire de Pharmacie, CHU Rennes, Rennes, France
- Univ Rennes, CHU Rennes, Inserm, EHESP, IRSET (Institut de recherche en santé, environnement et travail) - UMR_S 1085, Rennes, France
| | - Roxane Lhermitte
- Pôle Pharmacie, Service Hospitalo-Universitaire de Pharmacie, CHU Rennes, Rennes, France
| | - Brendan Le Daré
- Laboratoire de toxicologie et médico-légale, CHU Rennes, Rennes, France
- NSERM, INRAE, Institut NuMeCan (Nutrition, Metabolisms and Cancer), Réseau PREVITOX, Rennes 1 University, Rennes, France
| | - Marion Mercerolle
- Pôle Pharmacie, Service Hospitalo-Universitaire de Pharmacie, CHU Rennes, Rennes, France
| | - Cécile Vigneau
- Univ Rennes, CHU Rennes, Inserm, EHESP, IRSET (Institut de recherche en santé, environnement et travail) - UMR_S 1085, Rennes, France
| | - Pascal Le Corre
- Pôle Pharmacie, Service Hospitalo-Universitaire de Pharmacie, CHU Rennes, Rennes, France
- Univ Rennes, CHU Rennes, Inserm, EHESP, IRSET (Institut de recherche en santé, environnement et travail) - UMR_S 1085, Rennes, France
| | - Jonathan M Chemouny
- Univ Rennes, CHU Rennes, Inserm, EHESP, IRSET (Institut de recherche en santé, environnement et travail) - UMR_S 1085, Rennes, France
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12
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Knight SR. Transplant Trial Watch. Transpl Int 2023; 36:11129. [PMID: 36819124 PMCID: PMC9928744 DOI: 10.3389/ti.2023.11129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 01/12/2023] [Indexed: 02/04/2023]
Affiliation(s)
- Simon R Knight
- Oxford Transplant Centre, Churchill Hospital, Oxford, United Kingdom.,Centre for Evidence in Transplantation, Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom
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13
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Nelson J, Alvey N, Bowman L, Schulte J, Segovia M, McDermott J, Te HS, Kapila N, Levine DJ, Gottlieb RL, Oberholzer J, Campara M. Consensus recommendations for use of maintenance immunosuppression in solid organ transplantation: Endorsed by the American College of Clinical Pharmacy, American Society of Transplantation, and the International Society for Heart and Lung Transplantation. Pharmacotherapy 2022; 42:599-633. [DOI: 10.1002/phar.2716] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 03/29/2022] [Accepted: 04/08/2022] [Indexed: 12/17/2022]
Affiliation(s)
- Joelle Nelson
- Department of Pharmacotherapy and Pharmacy Services University Health San Antonio Texas USA
- Pharmacotherapy Education and Research Center University of Texas Health San Antonio San Antonio Texas USA
- Department of Pharmacy, Pharmacotherapy Division, College of Pharmacy The University of Texas at Austin Austin Texas USA
| | - Nicole Alvey
- Department of Pharmacy Rush University Medical Center Chicago Illinois USA
- Science and Pharmacy Roosevelt University College of Health Schaumburg Illinois USA
| | - Lyndsey Bowman
- Department of Pharmacy Tampa General Hospital Tampa Florida USA
| | - Jamie Schulte
- Department of Pharmacy Services Thomas Jefferson University Hospital Philadelphia Pennsylvania USA
| | | | - Jennifer McDermott
- Richard DeVos Heart and Lung Transplant Program, Spectrum Health Grand Rapids Michigan USA
- Department of Medicine, Michigan State University College of Human Medicine Grand Rapids Michigan USA
| | - Helen S. Te
- Liver Transplantation, Center for Liver Diseases, Department of Medicine University of Chicago Medical Center Chicago Illinois USA
| | - Nikhil Kapila
- Department of Transplant Hepatology Duke University Hospital Durham North Carolina USA
| | - Deborah Jo Levine
- Division of Critical Care Medicine, Department of Medicine The University of Texas Health Science Center at San Antonio San Antonio Texas USA
| | - Robert L. Gottlieb
- Baylor University Medical Center and Baylor Scott and White Research Institute Dallas Texas USA
| | - Jose Oberholzer
- Department of Surgery/Division of Transplantation University of Virginia Charlottesville Virginia USA
| | - Maya Campara
- Department of Surgery University of Illinois Chicago Chicago Illinois USA
- Department of Pharmacy Practice University of Illinois Chicago Chicago Illinois USA
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14
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Noorbakhsh S, Rahimzadeh N, Hosseini R, Otookesh H, Ehsanpoor F, Aminpour Y. Early Postoperative Kidney Transplant Complications Related to Immunomodulator Regimen in Pediatric Recipients. EXP CLIN TRANSPLANT 2022; 20:663-667. [DOI: 10.6002/ect.2021.0363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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15
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Risk Factors of Rejection in Renal Transplant Recipients: A Narrative Review. J Clin Med 2022; 11:jcm11051392. [PMID: 35268482 PMCID: PMC8911293 DOI: 10.3390/jcm11051392] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 02/25/2022] [Accepted: 02/28/2022] [Indexed: 12/14/2022] Open
Abstract
Multiple factors influence graft rejection after kidney transplantation. Pre-operative factors affecting graft function and survival include donor and recipient characteristics such as age, gender, race, and immunologic compatibility. In addition, several peri- and post-operative parameters affect graft function and rejection, such as cold and warm ischemia times, and post-operative immunosuppressive treatment. Exposure to non-self-human leucocyte antigens (HLAs) prior to transplantation up-regulates the recipient’s immune system. A higher rate of acute rejection is observed in transplant recipients with a history of pregnancies or significant exposure to blood products because these patients have higher panel reactive antibody (PRA) levels. Identifying these risk factors will help physicians to reduce the risk of allograft rejection, thereby promoting graft survival. In the current review, we summarize the existing literature on donor- and recipient-related risk factors of graft rejection and graft loss following kidney transplantation.
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16
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Yousif E, Abdelwahab A. Post-transplant Diabetes Mellitus in Kidney Transplant Recipients in Sudan: A Comparison Between Tacrolimus and Cyclosporine-Based Immunosuppression. Cureus 2022; 14:e22285. [PMID: 35350492 PMCID: PMC8932594 DOI: 10.7759/cureus.22285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/16/2022] [Indexed: 11/05/2022] Open
Abstract
Hyperglycemia is a common complication among transplant patients without a history of diabetes mellitus (DM). Although new and potent immunosuppressants have improved short and long-term outcomes after transplantation, these drugs themselves may be associated with a greater risk of hyperglycemia. The present study aimed to determine the prevalence of post-transplant diabetes mellitus (PTDM) in post renal transplant patients in Sudan, and compare the effect of cyclosporine and tacrolimus-based immunosuppressive regimens. All adult kidney transplant recipients without pre-transplant diabetes who attended the transplant clinic at Ahmed Gasim Cardiac Surgery and Renal Transplant Center in Sudan were included. A total of 100 cases with functioning kidney allografts were enrolled in this study. The majority of cases were in the age range between 20 and 60 years (92%). Males and females were nearly equally distributed (56% vs 44%). Fifty-two percent of patients were on cyclosporine and 48% on tacrolimus. Overall, 18% of patients suffered from post-transplant diabetes mellitus. There was no statistically significant difference between tacrolimus and cyclosporine with regards to the prevalence of hyperglycemia (16.6% versus 13.4%; p>0.05).
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Affiliation(s)
- Elamein Yousif
- Internal Medicine, Al Ahli Hospital, Doha, QAT
- Department of Nephrology, Ahmed Gasim Hospital, Khartoum, SDN
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17
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Ducloux D, Courivaud C. Prevention of Post-Transplant Diabetes Mellitus: Towards a Personalized Approach. J Pers Med 2022; 12:116. [PMID: 35055431 PMCID: PMC8778007 DOI: 10.3390/jpm12010116] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 01/06/2022] [Accepted: 01/13/2022] [Indexed: 02/01/2023] Open
Abstract
Post-transplant diabetes is a frequent complication after transplantation. Moreover, patients suffering from post-transplant diabetes have increased cardiovascular morbidity and reduced survival. Pathogenesis mainly involves beta-cell dysfunction in presence of insulin resistance. Both pre- and post-transplant risk factors are well-described, and some of them may be corrected or prevented. However, the frequency of post-transplant diabetes has not decreased in recent years. We realized a critical appraisal of preventive measures to reduce post-transplant diabetes.
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Affiliation(s)
- Didier Ducloux
- CHU Besançon, Department of Nephrology, Dialysis and Renal Transplantation, Federation Hospitalo-Universitaire INCREASE, 25000 Besançon, France;
- UMR RIGHT 1098, INSERM-EFS-UFC, 1 Bd Fleming, 25000 Besançon, France
| | - Cécile Courivaud
- CHU Besançon, Department of Nephrology, Dialysis and Renal Transplantation, Federation Hospitalo-Universitaire INCREASE, 25000 Besançon, France;
- UMR RIGHT 1098, INSERM-EFS-UFC, 1 Bd Fleming, 25000 Besançon, France
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18
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Angelico R, Blasi F, Manzia TM, Toti L, Tisone G, Cacciola R. The Management of Immunosuppression in Kidney Transplant Recipients with COVID-19 Disease: An Update and Systematic Review of the Literature. MEDICINA (KAUNAS, LITHUANIA) 2021; 57:435. [PMID: 33946462 PMCID: PMC8147172 DOI: 10.3390/medicina57050435] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 04/22/2021] [Accepted: 04/28/2021] [Indexed: 02/05/2023]
Abstract
Background and Objectives: In the era of the coronavirus disease 2019 (COVID-19) pandemic, the management of immunosuppressive (IS) therapy in kidney transplant (KT) recipients affected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires attention. It is not yet understood whether IS therapy may protect from the cytokine storm induced by SARS-CoV-2 infection or a temporary adjustment/withdrawal of IS therapy to restore the immune system may be necessary. We performed a systematic literature review to investigate the current management of IS therapy in KT recipients with COVID-1. Materials and Methods: Out of 71 articles published from 1 February 2020 until 30 October 2020, 554 KT recipients with SARS-CoV-2 infection were identified. Results: Modifications of IS therapy were based on the clinical conditions. For asymptomatic patients or those with mild COVID-19 symptoms, a "wait and see approach" was mostly used; a suspension of antimetabolites drugs (347/461, 75.27%) or mTOR inhibitors (38/48, 79.2%) was adopted in the majority of patients with symptomatic COVID-19 infections. For CNIs, the most frequent attitude was their maintenance (243/502, 48.4%) or dose-reduction (99/502, 19.72%) in patients asymptomatic or with mild COVID-19 symptoms, while drug withdrawal was the preferred choice in severely symptomatic patients (160/450, 31.87%). A discontinuation of all IS drugs was used only in severely symptomatic COVID-19 patients on invasive mechanical ventilation. Renal function remained stable in 422(76.17%) recipients, while 49(8.84%) patients experienced graft loss. Eight (1.44%) patients experienced a worsening of renal function. The overall mortality was 21.84%, and 53(9.56%) patients died with functioning grafts. Conclusion: A tailored approach to the patient has been the preferred strategy for the management of IS therapy in KT recipients, taking into account the clinical conditions of patients and the potential interactions between IS and antiviral drugs, in the attempt to balance the risks of COVID-19-related complications and those due to rejection or graft loss.
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Affiliation(s)
- Roberta Angelico
- Department of Surgery Sciences, Transplant and HPB Unit, University of Rome Tor Vergata, 00133 Rome, Italy; (R.A.); (F.B.); (L.T.); (G.T.); (R.C.)
| | - Francesca Blasi
- Department of Surgery Sciences, Transplant and HPB Unit, University of Rome Tor Vergata, 00133 Rome, Italy; (R.A.); (F.B.); (L.T.); (G.T.); (R.C.)
| | - Tommaso Maria Manzia
- Department of Surgery Sciences, Transplant and HPB Unit, University of Rome Tor Vergata, 00133 Rome, Italy; (R.A.); (F.B.); (L.T.); (G.T.); (R.C.)
| | - Luca Toti
- Department of Surgery Sciences, Transplant and HPB Unit, University of Rome Tor Vergata, 00133 Rome, Italy; (R.A.); (F.B.); (L.T.); (G.T.); (R.C.)
| | - Giuseppe Tisone
- Department of Surgery Sciences, Transplant and HPB Unit, University of Rome Tor Vergata, 00133 Rome, Italy; (R.A.); (F.B.); (L.T.); (G.T.); (R.C.)
| | - Roberto Cacciola
- Department of Surgery Sciences, Transplant and HPB Unit, University of Rome Tor Vergata, 00133 Rome, Italy; (R.A.); (F.B.); (L.T.); (G.T.); (R.C.)
- Department of Surgery, King Salman Armed Forces Hospital, Tabuk 47512, Saudi Arabia
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19
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Infante B, Bellanti F, Correale M, Pontrelli P, Franzin R, Leo S, Calvaruso M, Mercuri S, Netti GS, Ranieri E, Brunetti ND, Grandaliano G, Gesualdo L, Serviddio G, Castellano G, Stallone G. mTOR inhibition improves mitochondria function/biogenesis and delays cardiovascular aging in kidney transplant recipients with chronic graft dysfunction. Aging (Albany NY) 2021; 13:8026-8039. [PMID: 33758105 PMCID: PMC8034974 DOI: 10.18632/aging.202863] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 03/03/2021] [Indexed: 02/05/2023]
Abstract
CVD remains the major cause of mortality with graft functioning in Kidney transplant recipients (KTRs), with an estimated risk of CV events about 50-fold higher than in the general population. Many strategies have been considered to reduce the CV risk such as the use of mTOR inhibitors. We evaluate whether chronic mTOR inhibition might influence CV aging in KTRs studying the molecular mechanisms involved in this effect. We retrospectively analyzed 210 KTRs with stable graft function on therapy with CNI and mycophenolic acid (Group A, 105 pts.), or with CNI and mTORi (Everolimus, Group B, 105 pts.). The presence of mTOR inhibitor in immunosuppressive therapy was associated to increase serum levels of Klotho with concomitant reduction in FGF-23, with a significant decrease in left ventricular mass. In addition, KTRs with mTORi improved mitochondrial function/biogenesis in PBMC with more efficient oxidative phosphorylation, antioxidant capacity and glutathione peroxidase activity. Finally, group B KTRs presented reduced levels of inflammaging markers such as reduced serum pentraxin-3 and p21ink expression in PBMC. In conclusion, we demonstrated that mTOR inhibition in immunosuppressive protocols prevents the occurrence and signs of CV aging in KTRs.
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Affiliation(s)
- Barbara Infante
- Department of Medical and Surgical Sciences, Nephrology, Dialysis and Transplantation Unit, University of Foggia, Foggia, Italy
| | - Francesco Bellanti
- C.U.R.E. (University Center for Liver Disease Research and Treatment), Department of Medical and Surgical Sciences, University of Foggia, Italy
| | - Michele Correale
- Cardiology Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Paola Pontrelli
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari “Aldo Moro”, Bari, Italy
| | - Rossana Franzin
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari “Aldo Moro”, Bari, Italy
| | - Serena Leo
- Department of Medical and Surgical Sciences, Nephrology, Dialysis and Transplantation Unit, University of Foggia, Foggia, Italy
| | - Martina Calvaruso
- Department of Medical and Surgical Sciences, Nephrology, Dialysis and Transplantation Unit, University of Foggia, Foggia, Italy
| | - Silvia Mercuri
- Department of Medical and Surgical Sciences, Nephrology, Dialysis and Transplantation Unit, University of Foggia, Foggia, Italy
| | - Giuseppe Stefano Netti
- Department of Medical and Surgical Sciences, Nephrology, Dialysis and Transplantation Unit, University of Foggia, Foggia, Italy
| | - Elena Ranieri
- Clinical Pathology Unit and Center for Molecular Medicine, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Natale Daniele Brunetti
- Cardiology Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Giuseppe Grandaliano
- Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
- Università Cattolica del Sacro Cuore, Rome, Italy
| | - Loreto Gesualdo
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari “Aldo Moro”, Bari, Italy
| | - Gaetano Serviddio
- C.U.R.E. (University Center for Liver Disease Research and Treatment), Department of Medical and Surgical Sciences, University of Foggia, Italy
| | - Giuseppe Castellano
- Department of Medical and Surgical Sciences, Nephrology, Dialysis and Transplantation Unit, University of Foggia, Foggia, Italy
| | - Giovanni Stallone
- Department of Medical and Surgical Sciences, Nephrology, Dialysis and Transplantation Unit, University of Foggia, Foggia, Italy
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20
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Kim HD, Chang JY, Chung BH, Kim CD, Lee SH, Kim YH, Yang CW. Effect of Everolimus with Low-Dose Tacrolimus on Development of New-Onset Diabetes After Transplantation and Allograft Function in Kidney Transplantation: A Multicenter, Open-Label, Randomized Trial. Ann Transplant 2021; 26:e927984. [PMID: 33479188 PMCID: PMC7836319 DOI: 10.12659/aot.927984] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Background This randomized controlled trial aimed to investigate the effect of everolimus (EVL) with low-dose tacrolimus (Tac) on the development of post-transplantation diabetes mellitus (PTDM) in kidney transplantation (KT). Material/Methods Seventy-seven kidney transplant patients from 4 transplant centers were included. Patients were randomized to the “EVL group” (n=38) and the “TAC group” (n=39). The target Tac trough level was 2 to 5 ng/mL in the EVL group and 5 to 10 ng/mL in the TAC group. Results The 1-year cumulative incidence of PTDM in all patients was 7.8%, and no difference was found between the 2 groups (P=0.0819). Insulin resistance measured with the homeostatic model assessment for insulin resistance showed a significant increase only in the TAC group (1.11 to 1.30, P=0.0492). Allograft rejection rate and estimated glomerular filtration rate (eGFR) follow-ups every 3 months were not significantly different between the 2 groups. However, the EVL group showed a significant increase in the mean eGFR at 9 months and 12 months after KT compared to the baseline value (P=0.0242 and 0.0491, respectively). The EVL group showed lower insulin resistance and higher allograft function in comparison to the TAC group. Conclusions EVL-based immunosuppressive therapy with lower Tac exposure could be a safer alternative for maintenance treatment.
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Affiliation(s)
- Hyung Duk Kim
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Ji-Yeun Chang
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Byung Ha Chung
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Chan-Duck Kim
- Department of Internal Medicine, Kyungpook National University School of Medicine, Deagu, South Korea
| | - Sang-Ho Lee
- Department of Internal Medicine, College of Medicine, Kyung Hee University, Seoul, South Korea
| | - Yeong Hoon Kim
- Department of Internal Medicine, College of Medicine, Inje University, Pusan, South Korea
| | - Chul Woo Yang
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, South Korea
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21
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Hecking M, Sharif A, Eller K, Jenssen T. Management of post-transplant diabetes: immunosuppression, early prevention, and novel antidiabetics. Transpl Int 2021; 34:27-48. [PMID: 33135259 PMCID: PMC7839745 DOI: 10.1111/tri.13783] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 08/20/2020] [Accepted: 10/29/2020] [Indexed: 12/12/2022]
Abstract
Post-transplant diabetes mellitus (PTDM) shows a relationship with risk factors including obesity and tacrolimus-based immunosuppression, which decreases pancreatic insulin secretion. Several of the sodium-glucose-linked transporter 2 inhibitors (SGLT2is) and glucagon-like peptide 1 receptor agonists (GLP1-RAs) dramatically improve outcomes of individuals with type 2 diabetes with and without chronic kidney disease, which is, as heart failure and atherosclerotic cardiovascular disease, differentially affected by both drug classes (presumably). Here, we discuss SGLT2is and GLP1-RAs in context with other PTDM management strategies, including modification of immunosuppression, active lifestyle intervention, and early postoperative insulin administration. We also review recent studies with SGLT2is in PTDM, reporting their safety and antihyperglycemic efficacy, which is moderate to low, depending on kidney function. Finally, we reference retrospective case reports with GLP1-RAs that have not brought forth major concerns, likely indicating that GLP1-RAs are ideal for PTDM patients suffering from obesity. Although our article encompasses PTDM after solid organ transplantation in general, data from kidney transplant recipients constitute the largest proportion. The PTDM research community still requires data that treating and preventing PTDM will improve clinical conditions beyond hyperglycemia. We therefore suggest that it is time to collaborate, in testing novel antidiabetics among patients of all transplant disciplines.
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Affiliation(s)
- Manfred Hecking
- Department of Internal Medicine IIIClinical Division of Nephrology & DialysisMedical University of ViennaViennaAustria
| | - Adnan Sharif
- Department of Nephrology and TransplantationQueen Elizabeth HospitalBirminghamUK
| | - Kathrin Eller
- Clinical Division of NephrologyMedical University of GrazGrazAustria
| | - Trond Jenssen
- Department of Organ TransplantationOslo University HospitalRikshospitaletOsloNorway
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22
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Hansrivijit P, Puthenpura MM, Thongprayoon C, Brar HS, Bathini T, Kovvuru K, Kanduri SR, Wijarnpreecha K, Cheungpasitporn W. Incidence and Impacts of Inflammatory Bowel Diseases among Kidney Transplant Recipients: A Meta-Analysis. Med Sci (Basel) 2020; 8:medsci8030039. [PMID: 32947774 PMCID: PMC7565568 DOI: 10.3390/medsci8030039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 08/30/2020] [Accepted: 08/31/2020] [Indexed: 11/16/2022] Open
Abstract
Background: The incidence of inflammatory bowel diseases (IBD) and its significance in kidney transplant recipients is not well established. We conducted this systematic review and meta-analysis to assess the incidence of and complications from IBD in adult kidney transplant recipients. Methods: Eligible articles were searched through Ovid MEDLINE, EMBASE, and the Cochrane Library from inception through April 2020. The inclusion criteria were adult kidney transplant patients with reported IBD. Effect estimates from the individual studies were extracted and combined using the fixed-effects model when I2 ≤ 50% and random-effects model when I2 > 50%. Results: of 641 citations, a total of seven studies (n = 212) were included in the systematic review. The mean age was 46.2 +/− 6.9 years and up to 51.1% were male. The mean duration of follow-up was 57.8 +/− 16.8 months. The pooled incidence of recurrent IBD was 27.6% (95% CI, 17.7–40.5%; I2 0%) while the pooled incidence of de novo IBD was 18.8% (95% CI, 10.7–31.0%; I2 61.3%). The pooled incidence of post-transplant IBD was similar across subgroup analyses. Meta-regression analyses showed no association between the incidence of IBD and age, male sex, and follow-up duration. For post-transplant complications, the pooled incidence of post-transplant infection was 4.7% (95% CI, 0.5–33.3%; I2 73.7%). The pooled incidence of graft rejection and re-transplantation in IBD patients was 31.4% (95% CI, 14.1–56.1%; I2 76.9%) and 30.4% (95% CI, 22.6–39.5%; I2 0%). Conclusion: Recurrent and de novo IBD is common among kidney transplant recipients and may result in adverse outcomes.
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Affiliation(s)
| | - Max M. Puthenpura
- Department of Medicine, Drexel University College of Medicine, Philadelphia, PA 19129, USA;
| | - Charat Thongprayoon
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA
- Correspondence: (C.T.); (W.C.)
| | - Himmat S. Brar
- Department of Internal Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA;
| | - Tarun Bathini
- Department of Internal Medicine, University of Arizona, Tucson, AZ 85721, USA;
| | - Karthik Kovvuru
- Department of Medicine, Ochsner Medical Center, New Orleans, LA 70121, USA; (K.K.); (S.R.K.)
| | - Swetha R. Kanduri
- Department of Medicine, Ochsner Medical Center, New Orleans, LA 70121, USA; (K.K.); (S.R.K.)
| | - Karn Wijarnpreecha
- Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Jacksonville, FL 32224, USA;
| | - Wisit Cheungpasitporn
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA
- Correspondence: (C.T.); (W.C.)
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23
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Takaki T, Shimoda M. Pancreatic islet transplantation: toward definitive treatment for diabetes mellitus. Glob Health Med 2020; 2:200-211. [PMID: 33330809 DOI: 10.35772/ghm.2020.01057] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 07/31/2020] [Accepted: 08/03/2020] [Indexed: 12/27/2022]
Abstract
Since the late 20th century, advances in pancreatic islet transplantation have targeted improved glycemic control and fewer hypoglycemic events in patients with type 1 diabetes, and some important milestones have been reached. Following the Edmonton group's success in achieving insulin independence in all transplanted patients with type 1 diabetes, clinical islet transplantation is now performed worldwide. β cell replacement therapy for type 1 diabetes was established based on the favorable outcomes of a phase 3, prospective, open-label, single-arm, clinical study conducted at 8 centers in North America, in which 42 of 48 patients who underwent islet transplantation from 2008 to 2011 achieved HbA1c < 7.0% (53 mmol/mol) at day 365, which was maintained at 2 years in 34 patients. In Japan, a phase 2 multicenter clinical trial of islet transplantation for type 1 diabetes patients is currently ongoing and will end soon, but the interim results have already led to positive changes, with allogeneic islet transplantation being covered by the national health insurance system since April 2020. Current efforts are being made to solve the problem of donor shortage by studying alternative donor sources, such as porcine islets and pancreatic progenitor cells derived from pluripotent stem cells. The results of clinical trials in this area are eagerly awaited. It is hoped that they will contribute to establishing alternative sources for insulin-producing β cells in the near future.
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Affiliation(s)
- Tadashi Takaki
- Department of Pancreatic Islet Cell Transplantation, National Center for Global Health and Medicine, Tokyo, Japan.,Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.,Takeda-CiRA Joint Program for iPS Cell Applications (T-CiRA), Fujisawa, Kanagawa, Japan
| | - Masayuki Shimoda
- Department of Pancreatic Islet Cell Transplantation, National Center for Global Health and Medicine, Tokyo, Japan
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Cohen JB, Lim MA, Tewksbury CM, Torres-Landa S, Trofe-Clark J, Abt PL, Williams NN, Dumon KR, Goral S. Bariatric surgery before and after kidney transplantation: long-term weight loss and allograft outcomes. Surg Obes Relat Dis 2020; 15:935-941. [PMID: 31378281 DOI: 10.1016/j.soard.2019.04.002] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2018] [Revised: 03/27/2019] [Accepted: 04/02/2019] [Indexed: 01/03/2023]
Abstract
BACKGROUND Severe obesity is frequently a barrier to kidney transplantation, and kidney transplant recipients often have significant weight gain following transplantation. OBJECTIVES The goals of this study were to evaluate the long-term risks and benefits of bariatric surgery before and after kidney transplantation. SETTING University Hospital, United States. METHODS We performed a retrospective cohort study of 43 patients who had pretransplantation bariatric surgery and 21 patients who had posttransplantation bariatric surgery from 1994 to 2017 with propensity-score matching to identify matched controls using national registry data. RESULTS Body mass index at the time of transplantation was similar in patients who underwent bariatric surgery before versus after transplantation (32 versus 34 kg/m2, P = .172). There was no significant difference in body mass index in the 5 years after bariatric surgery among patients who underwent bariatric surgery before versus after kidney transplantation (36 versus 32 kg/m2, P = 0.814). Compared with matched controls, bariatric surgery before (n = 38) and after (n = 18) kidney transplantation was associated with a decreased risk of allograft failure (hazard ratio .31 [95% confidence interval .29-0.33] and .85 [95% confidence interval .85-.86] for pre- and posttransplant, respectively) and mortality (hazard ratio .57 [95% confidence interval .53-.61] and .80 [95% confidence interval .79-.82] for pre- and posttransplant, respectively). CONCLUSIONS Bariatric surgery before and after kidney transplantation results in similar maintenance of weight loss and improved long-term allograft survival compared with matched controls. Bariatric surgery appears to be a safe and reasonable approach to weight loss both before and after transplantation.
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Affiliation(s)
- Jordana B Cohen
- Renal-Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Center for Clinical Epidemiology and Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.
| | - Mary Ann Lim
- Renal-Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Colleen M Tewksbury
- Penn Metabolic and Bariatric Surgery Program, Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Samuel Torres-Landa
- Penn Metabolic and Bariatric Surgery Program, Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Jennifer Trofe-Clark
- Renal-Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Department of Pharmacy Services, Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Peter L Abt
- Division of Transplant Surgery, Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Noel N Williams
- Penn Metabolic and Bariatric Surgery Program, Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Kristoffel R Dumon
- Penn Metabolic and Bariatric Surgery Program, Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Simin Goral
- Renal-Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
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25
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Hannachi I, Ben Fredj N, Chadli Z, Ben Fadhel N, Ben Romdhane H, Touitou Y, Boughattas NA, Chaabane A, Aouam K. Effect of CYP3A4*22 and CYP3A4*1B but not CYP3A5*3 polymorphisms on tacrolimus pharmacokinetic model in Tunisian kidney transplant. Toxicol Appl Pharmacol 2020; 396:115000. [DOI: 10.1016/j.taap.2020.115000] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2019] [Revised: 03/18/2020] [Accepted: 04/05/2020] [Indexed: 12/16/2022]
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26
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Ali H, Soliman KM, Shaheen I, Kim JJ, Kossi ME, Sharma A, Pararajasingam R, Halawa A. Rabbit anti-thymocyte globulin (rATG) versus IL-2 receptor antagonist induction therapies in tacrolimus-based immunosuppression era: a meta-analysis. Int Urol Nephrol 2020; 52:791-802. [PMID: 32170593 DOI: 10.1007/s11255-020-02418-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Accepted: 02/17/2020] [Indexed: 01/25/2023]
Abstract
BACKGROUND The aim of this meta-analysis is to explore the effect of IL-2RA vs rATG on the rate of acute rejection, post-transplant infections, and graft as well as patient's survival in standard- and high-risk renal transplant patients receiving tacrolimus-based maintenance immunotherapy. METHODS Random effects model was the method used for identifying risk difference. Confidence interval including the value 1 was used as evidence for statistically significant risk difference. Heterogeneity was assessed using Der Simonian analysis. Heterogeneity was evident at the level of P value < 0.1 RESULTS: The random effects model showed no significant differences in both acute rejection rates between IL-2RA and rATG induction therapies with relative risk of 1.24 graft survival with relative risk 0.90. Patient survival also did not demonstrate any significant difference with a relative risk of 1.19. Random effects for CMV infection showed a lesser tendency for CMV infection in IL-2RA group compared to ATG group the with a relative risk of 0.73.In subgroup analysis, the random effects model for acute rejection rates in high-risk transplants showed a higher risk of acute rejection in the IL-2RA group compared to rATG (relative risk equals 1.55) In standard-risk transplants, there were no significant differences between both groups with relative risk equals 1.02 CONCLUSIONS: This meta-analysis revealed no significant difference in patient and graft survival when using IL-2RA vs rATG with the tacrolimus-based maintenance immunosuppression era. However, subgroup analysis showed less incidence of rejection in high-risk renal transplant recipient's population using rATG compared to IL-2RA.
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Affiliation(s)
- Hatem Ali
- Department of Renal Medicine, Royal Stoke University Hospital, NHS Foundation Trust, Stoke-on-Trent, UK.,Faculty of Medicine, Institute of Medical Sciences, University of Liverpool, Liverpool, UK
| | - Karim M Soliman
- Division of Nephrology, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA
| | - Ihab Shaheen
- Faculty of Medicine, Institute of Medical Sciences, University of Liverpool, Liverpool, UK.,Royal Hospital for Children, Glasgow, UK
| | - Jon Jin Kim
- Faculty of Medicine, Institute of Medical Sciences, University of Liverpool, Liverpool, UK.,Nottingham Children Hospital, Nottingham, UK
| | - Mohsen El Kossi
- Faculty of Medicine, Institute of Medical Sciences, University of Liverpool, Liverpool, UK.,Renal Department, Doncaster Royal Infirmary, Doncaster, UK
| | - Ajay Sharma
- Faculty of Medicine, Institute of Medical Sciences, University of Liverpool, Liverpool, UK.,Transplant Surgery Department, Royal Liverpool University Hospital, Liverpool, UK
| | - Ravi Pararajasingam
- Faculty of Medicine, Institute of Medical Sciences, University of Liverpool, Liverpool, UK.,Transplant Surgery Department, Sheffield Kidney Institute, Sheffield Teaching Hospitals, Sheffield, UK
| | - Ahmed Halawa
- Faculty of Medicine, Institute of Medical Sciences, University of Liverpool, Liverpool, UK. .,Transplant Surgery Department, Sheffield Kidney Institute, Sheffield Teaching Hospitals, Sheffield, UK.
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27
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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.
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28
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DuBay DA, Teperman L, Ueda K, Silverman A, Chapman W, Alsina AE, Tyler C, Stevens DR. Pharmacokinetics of Once-Daily Extended-Release Tacrolimus Tablets Versus Twice-Daily Capsules in De Novo Liver Transplant. Clin Pharmacol Drug Dev 2019; 8:995-1008. [PMID: 30667591 PMCID: PMC6899533 DOI: 10.1002/cpdd.657] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Accepted: 12/28/2018] [Indexed: 11/26/2022]
Abstract
The pharmacokinetics of once-daily extended-release tacrolimus tablets (LCPT) in de novo liver transplantation have not been previously reported. In this phase II, randomized, open-label study, de novo liver transplant recipients were randomized to LCPT 0.07-0.13 mg/kg/day (taken once daily; n = 29) or twice-daily immediate-release tacrolimus capsules (IR-Tac) at 0.10-0.15 mg/kg/day (divided twice daily; n = 29). Subsequent doses of both drugs were adjusted to maintain tacrolimus trough concentrations of 5 to 20 ng/mL through day 90, and 5-15 ng/mL thereafter. Twenty-four-hour pharmacokinetic profiles were obtained on days 1, 7, and 14, with trough concentration and efficacy/safety monitoring through year 1. Similar proportions of patients in both groups achieved therapeutic trough concentrations on days 7 and 14 (day 7: LCPT = 78%, IR-Tac = 75%; day 14: LCPT = 86%, IR-Tac = 91%) as well as similar systemic and peak exposure. There was a robust correlation between drug concentration at time 0 and area under the concentration-time curve for both LCPT and IR-Tac (respectively, day 7: r = 0.86 and 0.79; day 14: r = 0.93 and 0.86; P < .0001 for all). Dose adjustments during days 1 to 14 were frequent. Thirty-five patients completed the extended-use period. No significant differences in adverse events were seen between groups. Incidence of biopsy-proven acute rejection (LCPT = 6 and IR-Tac = 4) was similar on day 360. Between formulations, overall exposure was similar at 1 week after transplant with the characteristic delayed-release pharmacokinetic profile of LCPT demonstrated in this novel population. These data support further investigation of the safety and efficacy of LCPT in de novo liver transplantation.
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Affiliation(s)
- Derek A DuBay
- Medical University of South Carolina, Department of Surgery, Charleston, SC, USA
| | | | - Kimi Ueda
- California Pacific Medical Center, San Francisco, CA, USA
| | | | - William Chapman
- Washington University School of Medicine, Department of Surgery, St Louis, MO, USA
| | - Angel E Alsina
- Tampa General Hospital, Division of Transplantation, Tampa, FL, USA
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Soares ROS, Losada DM, Jordani MC, Évora P, Castro-E-Silva O. Ischemia/Reperfusion Injury Revisited: An Overview of the Latest Pharmacological Strategies. Int J Mol Sci 2019; 20:ijms20205034. [PMID: 31614478 PMCID: PMC6834141 DOI: 10.3390/ijms20205034] [Citation(s) in RCA: 239] [Impact Index Per Article: 39.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Revised: 10/03/2019] [Accepted: 10/08/2019] [Indexed: 02/08/2023] Open
Abstract
Ischemia/reperfusion injury (IRI) permeates a variety of diseases and is a ubiquitous concern in every transplantation proceeding, from whole organs to modest grafts. Given its significance, efforts to evade the damaging effects of both ischemia and reperfusion are abundant in the literature and they consist of several strategies, such as applying pre-ischemic conditioning protocols, improving protection from preservation solutions, thus providing extended cold ischemia time and so on. In this review, we describe many of the latest pharmacological approaches that have been proven effective against IRI, while also revisiting well-established concepts and presenting recent pathophysiological findings in this ever-expanding field. A plethora of promising protocols has emerged in the last few years. They have been showing exciting results regarding protection against IRI by employing drugs that engage several strategies, such as modulating cell-surviving pathways, evading oxidative damage, physically protecting cell membrane integrity, and enhancing cell energetics.
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Affiliation(s)
| | - Daniele M Losada
- Department of Anatomic Pathology, Faculty of Medical Sciences, University of Campinas, 13083-970 Campinas, Brazil.
| | - Maria C Jordani
- Department of Surgery & Anatomy, Ribeirão Preto Medical School, University of São Paulo, 14049-900 Ribeirão Preto, Brazil.
| | - Paulo Évora
- Department of Surgery & Anatomy, Ribeirão Preto Medical School, University of São Paulo, 14049-900 Ribeirão Preto, Brazil.
- Department of Gastroenterology, São Paulo Medical School, University of São Paulo, 01246-903 São Paulo, Brazil.
| | - Orlando Castro-E-Silva
- Department of Surgery & Anatomy, Ribeirão Preto Medical School, University of São Paulo, 14049-900 Ribeirão Preto, Brazil.
- Department of Gastroenterology, São Paulo Medical School, University of São Paulo, 01246-903 São Paulo, Brazil.
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Abstract
Neurologic disturbances including encephalopathy, seizures, and focal deficits complicate the course 10-30% of patients undergoing organ or stem cell transplantation. While much or this morbidity is multifactorial and often associated with extra-cerebral dysfunction (e.g., graft dysfunction, metabolic derangements), immunosuppressive drugs also contribute significantly. This can either be through direct toxicity (e.g., posterior reversible encephalopathy syndrome from calcineurin inhibitors such as tacrolimus in the acute postoperative period) or by facilitating opportunistic infections in the months after transplantation. Other neurologic syndromes such as akinetic mutism and osmotic demyelination may also occur. While much of this neurologic dysfunction may be reversible if related to metabolic factors or drug toxicity (and the etiology is recognized and reversed), cases of multifocal cerebral infarction, hemorrhage, or infection may have poor outcomes. As transplant patients survive longer, delayed infections (such as progressive multifocal leukoencephalopathy) and post-transplant malignancies are increasingly reported.
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Lin YC, Tsai CS, Li IH, Tsai YT, Huang TY, Lee KF, Lin CS, Shih JH, Kao LT. Transplant Recipients Using Tacrolimus Had Higher Utilization of Healthcare Services Than Those Receiving Cyclosporine in Taiwan. Front Pharmacol 2019; 10:1074. [PMID: 31607922 PMCID: PMC6761300 DOI: 10.3389/fphar.2019.01074] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Accepted: 08/23/2019] [Indexed: 12/27/2022] Open
Abstract
To date, population-based studies on the healthcare service utilization among stable heart, kidney, and liver transplant recipients with different calcineurin inhibitors are still scarce. Therefore, we used the Taiwan National Health Insurance Research Database to conduct a nationwide cross-sectional study to estimate the healthcare utilization of stable transplant recipients with tacrolimus or cyclosporine (n = 3,482). The sampled patients in this study comprised 377 heart, 1,693 kidney, and 1,412 liver transplant recipients between 1 January 2011 and 31 December 2011. Each subject was followed for a 1-year period to evaluate his/her healthcare service utilization. Outcome variables of the healthcare service utilization were stated as below: numbers of outpatient visits, outpatient costs, numbers of inpatient days, inpatients costs, and total costs of all healthcare services. As for all healthcare service utilization, stable transplant recipients on tacrolimus had significantly more outpatient visits (40.7 vs. 38.6), outpatient costs (US$10,383 vs. US$8,155), and total costs (US$12,516 vs. US$10,372) of all healthcare services than those on cyclosporine during the 1-year follow-up period. Additionally, further analysis showed that heart transplant recipients receiving tacrolimus incurred 1.7-fold higher inpatient costs compared to patients receiving cyclosporine. We concluded that transplant recipients using tacrolimus had significantly higher utilization of all healthcare services than those receiving cyclosporine as immunosuppressive therapy.
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Affiliation(s)
- Yi-Chang Lin
- Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan.,Division of Cardiovascular Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Chien-Sung Tsai
- Division of Cardiovascular Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - I-Hsun Li
- Department of Pharmacy Practice, Tri-Service General Hospital, Taipei, Taiwan.,School of Pharmacy, National Defense Medical Center, Taipei, Taiwan
| | - Yi-Ting Tsai
- Division of Cardiovascular Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Tien-Yu Huang
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Kwai-Fong Lee
- Biobank Management Center, Tri-Service General Hospital, Taipei, Taiwan.,School of Public Health, National Defense Medical Center, Taipei, Taiwan
| | - Chih-Sheng Lin
- Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan
| | - Jui-Hu Shih
- Department of Pharmacy Practice, Tri-Service General Hospital, Taipei, Taiwan.,School of Pharmacy, National Defense Medical Center, Taipei, Taiwan
| | - Li-Ting Kao
- Department of Pharmacy Practice, Tri-Service General Hospital, Taipei, Taiwan.,School of Pharmacy, National Defense Medical Center, Taipei, Taiwan.,School of Public Health, National Defense Medical Center, Taipei, Taiwan.,Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan
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32
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Ali H, Mohiuddin A, Sharma A, Shaheen I, Kim JJ, El Kosi M, Halawa A. Implication of interleukin-2 receptor antibody induction therapy in standard risk renal transplant in the tacrolimus era: a meta-analysis. Clin Kidney J 2019; 12:592-599. [PMID: 31384453 PMCID: PMC6671558 DOI: 10.1093/ckj/sfy132] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Indexed: 12/30/2022] Open
Abstract
Background Interleukin-2 (IL-2) antagonist has been used as an induction therapy in many centres in calcineurin inhibitor-sparing regimens. Tacrolimus has overwhelmingly replaced cyclosporine in the maintenance immunosuppressive protocols in many transplant centres. The aim of our study and meta-analysis is to explore the effect of IL-2 induction therapy on the rate of rejection and patient and graft survival in standard-risk renal transplant patients with tacrolimus-based maintenance immunotherapy. Secondary aims included assessment of the effect of IL-2 induction therapy on creatinine change and the risk of cytomegalovirus (CMV) infection. Methods We conducted a systematic review in different databases to identify studies and research work that assessed the effect of IL-2 antibody induction therapy on renal transplant outcomes. Inclusion criteria for our meta-analysis were all studies that compared IL-2 induction therapy with placebo or no induction therapy in standard-risk renal transplant recipients on tacrolimus-based maintenance immunosuppressive therapy. Data collected were the name of the first author, journal title, year of publication, country where the study was conducted, number of patients in the IL-2 induction therapy arm and in the placebo arm, number of patients who had biopsy-proven rejection and graft survival in each arm. A random effects model was used for the meta-analysis. Results Of the 470 articles found in different databases, 7 were included in the meta-analysis. Forest plot analysis for rate of rejection during the follow-up period post-transplant showed no significant difference between the groups. There was no evidence of heterogenicity between included studies (I 2 = 21.8%, P = 0.27). The overall risk difference was -0.02 [95% confidence interval (CI) -0.05-0.01]. A random effects meta-analysis for patient and graft survival was performed using forest plot analysis and showed no significant effect of IL-2 receptor (IL-2R) antibody induction on patient or graft survival compared with placebo. The overall risk difference was -0.01 (95% CI -0.04-0.01) and 0.00 (95% CI -0.00-0.01), respectively. Three of the included studies showed no effect of basiliximab on creatinine change, two showed no effect on risk of CMV infection and two showed less risk of post-transplant diabetes in the basiliximab group. Conclusion IL-2R antibody induction therapy has no significant effect on the rate of rejection or patient or graft survival in standard-risk renal transplant recipients on tacrolimus-based maintenance immunotherapy. More randomized controlled studies are needed.
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Affiliation(s)
- Hatem Ali
- Department of Renal Medicine, Royal Stoke University Hospital, NHS Foundation Trust, Stoke-on-Trent, UK.,Institute of Medical Sciences, Faculty of Medicine, University of Liverpool, Liverpool, UK
| | - Atif Mohiuddin
- Institute of Medical Sciences, Faculty of Medicine, University of Liverpool, Liverpool, UK.,Department of Transplantation, Liverpool University Teaching Hospital, NHS Foundation Trust, Liverpool, UK
| | - Ajay Sharma
- Institute of Medical Sciences, Faculty of Medicine, University of Liverpool, Liverpool, UK.,Department of Transplantation, Liverpool University Teaching Hospital, NHS Foundation Trust, Liverpool, UK
| | - Ihab Shaheen
- Institute of Medical Sciences, Faculty of Medicine, University of Liverpool, Liverpool, UK.,Royal Hospital for Sick Children, Glasgow, UK
| | - Jon Jin Kim
- Institute of Medical Sciences, Faculty of Medicine, University of Liverpool, Liverpool, UK.,Nottingham Children Hospital, Nottingham, UK
| | - Mohsen El Kosi
- Institute of Medical Sciences, Faculty of Medicine, University of Liverpool, Liverpool, UK.,Renal Department, Doncaster Royal Infirmary, Doncaster, UK
| | - Ahmed Halawa
- Institute of Medical Sciences, Faculty of Medicine, University of Liverpool, Liverpool, UK.,Department of Renal Medicine, Sheffield Kidney Institute, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
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Abstract
Kidney transplantation (KT) is the most effective way to decrease the high morbidity and mortality of patients with end-stage renal disease. However, KT does not completely reverse the damage done by years of decreased kidney function and dialysis. Furthermore, new offending agents (in particular, immunosuppression) added in the post-transplant period increase the risk of complications. Cardiovascular (CV) disease, the leading cause of death in KT recipients, warrants pre-transplant screening based on risk factors. Nevertheless, the screening methods currently used have many shortcomings and a perfect screening modality does not exist. Risk factor modification in the pre- and post-transplant periods is of paramount importance to decrease the rate of CV complications post-transplant, either by lifestyle modification (for example, diet, exercise, and smoking cessation) or by pharmacological means (for example, statins, anti-hyperglycemics, and so on). Post-transplantation diabetes mellitus (PTDM) is a major contributor to mortality in this patient population. Although tacrolimus is a major contributor to PTDM development, changes in immunosuppression are limited by the higher risk of rejection with other agents. Immunosuppression has also been implicated in higher risk of malignancy; therefore, proper cancer screening is needed. Cancer immunotherapy is drastically changing the way certain types of cancer are treated in the general population; however, its use post-transplant is limited by the risk of allograft rejection. As expected, higher risk of infections is also encountered in transplant recipients. When caring for KT recipients, special attention is needed in screening methods, preventive measures, and treatment of infection with BK virus and cytomegalovirus. Hepatitis C virus infection is common in transplant candidates and in the deceased donor pool; however, newly developed direct-acting antivirals have been proven safe and effective in the pre- and post-transplant periods. The most important and recent developments on complications following KT are reviewed in this article.
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Affiliation(s)
- Abraham Cohen-Bucay
- Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, 14080, Mexico.,Nephrology Department, American British Cowdray Medical Center, Mexico City, 05300, Mexico
| | - Craig E Gordon
- Division of Nephrology, Tufts Medical Center, Boston, MA, 02111, USA
| | - Jean M Francis
- Renal Section, Boston University Medical Center, Boston, MA, 02118, USA
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Ko DH, Cho EJ, Lee W, Chun S, Min WK. Accuracy evaluation of Roche and Siemens tacrolimus and cyclosporine assays in comparison with liquid chromatography-tandem mass spectrometry. Scandinavian Journal of Clinical and Laboratory Investigation 2018; 78:431-438. [PMID: 30270673 DOI: 10.1080/00365513.2018.1472801] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Therapeutic drug monitoring of tacrolimus and cyclosporine is crucial to the success of organ transplantation. We evaluated the analytical performances and accuracy of two commercially available tacrolimus and cyclosporine assays (Roche ISD and Siemens) in comparison with liquid chromatography-tandem mass spectrometry (LC-MS/MS). A total of 342 leftover whole blood samples requested for tacrolimus or cyclosporine assays were stored at -20 °C until analysis. Repeatability and between-run imprecision were evaluated using quality control materials provided by the manufacturer. Ring trial samples were used for the assessment of recovery. The results of the Roche ISD assay were compared with those of Siemens tacrolimus and cyclosporine assays and LC-MS/MS. Repeatability and between-run imprecision were 2.1-5.3% and 2.6-7.5%, respectively. Recovery of Roche ISD was 85.7 - 90.6% for cyclosporine and 96.2-98.5% for tacrolimus. The two immunoassays showed slight positive biases relative to LC-MS/MS for cyclosporine. For tacrolimus, Roche ISD produced virtually identical results to those of LC-MS/MS, whereas Siemens showed proportional differences, especially in patients receiving kidney transplantation. The analytical performances of Roche ISD were generally acceptable, especially regarding accuracy. Clinical laboratory staff should be aware of the strengths and weaknesses of commercial immunoassays in order to ensure accurate results.
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Affiliation(s)
- Dae-Hyun Ko
- a Department of Laboratory Medicine , Hallym University College of Medicine , Hwaseong , Korea
| | - Eun-Jung Cho
- b Department of Laboratory Medicine , University of Ulsan College of Medicine and Asan Medical Center , Seoul , Korea
| | - Woochang Lee
- b Department of Laboratory Medicine , University of Ulsan College of Medicine and Asan Medical Center , Seoul , Korea
| | - Sail Chun
- b Department of Laboratory Medicine , University of Ulsan College of Medicine and Asan Medical Center , Seoul , Korea
| | - Won-Ki Min
- b Department of Laboratory Medicine , University of Ulsan College of Medicine and Asan Medical Center , Seoul , Korea
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Qin X, Rui J, Xia Y, Mu H, Song SH, Raja Aziddin RE, Miles G, Sun Y, Chun S. Multi-center Performance Evaluations of Tacrolimus and Cyclosporine Electrochemiluminescence Immunoassays in the Asia-Pacific Region. Ann Lab Med 2018; 38:85-94. [PMID: 29214751 PMCID: PMC5736684 DOI: 10.3343/alm.2018.38.2.85] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2017] [Revised: 06/23/2017] [Accepted: 09/29/2017] [Indexed: 01/28/2023] Open
Abstract
Background The immunosuppressant drugs (ISDs), tacrolimus and cyclosporine, are vital for solid organ transplant patients to prevent rejection. However, toxicity is a concern, and absorption is highly variable across patients; therefore, ISD levels need to be precisely monitored. In the Asia-Pacific (APAC) region, tacrolimus and cyclosporine concentrations are typically measured using immunoassays. The objective of this study was to assess the analytical performance of Roche Elecsystacrolimus and cyclosporinee electrochemiluminescence immunoassays (ECLIAs). Methods This evaluation was performed in seven centers across China, South Korea, and Malaysia. Imprecision (repeatability and reproducibility), assay accuracy, and lot-to-lot reagent variability were tested. The Elecsys ECLIAs were compared with commercially available immunoassays (Architect, Dimension, and Viva-E systems) using whole blood samples from patients with various transplant types (kidney, liver, heart, and bone marrow). Results Coefficients of variation for repeatability and reproducibility were ≤5.4% and ≤12.4%, respectively, for the tacrolimus ECLIA, and ≤5.1% and ≤7.3%, respectively, for the cyclosporine ECLIA. Method comparisons of the tacrolimus ECLIA with Architect, Dimension, and Viva-E systems yielded slope values of 1.01, 1.14, and 0.897, respectively. The cyclosporine ECLIA showed even closer agreements with the Architect, Dimension, and Viva-E systems (slope values of 1.04, 1.04, and 1.09, respectively). No major differences were observed among the different transplant types. Conclusions The tacrolimus and cyclosporine ECLIAs demonstrated excellent precision and close agreement with other immunoassays tested. These results show that both assays are suitable for ISD monitoring in an APAC population across a range of different transplant types.
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Affiliation(s)
- Xuzhen Qin
- Peking Union Medical College Hospital, Beijing, China
| | - Jianzhong Rui
- Department of Pharmacology, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Yong Xia
- The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Hong Mu
- Tianjin First Center Hospital, Tianjin, China
| | - Sang Hoon Song
- Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Raja Elina Raja Aziddin
- Department of Pathology, Hospital Kuala Lumpur Drug and Research Laboratory, Kuala Lumpur, Malaysia
| | | | - Yuli Sun
- Roche Diagnostics, Penzberg, Germany
| | - Sail Chun
- Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
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Hu C, Yin WJ, Li DY, Ding JJ, Zhou LY, Wang JL, Ma RR, Liu K, Zhou G, Zuo XC. Evaluating tacrolimus pharmacokinetic models in adult renal transplant recipients with different CYP3A5 genotypes. Eur J Clin Pharmacol 2018; 74:1437-1447. [PMID: 30019212 DOI: 10.1007/s00228-018-2521-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Accepted: 07/06/2018] [Indexed: 10/28/2022]
Abstract
PURPOSE Numerous studies have been conducted on the population pharmacokinetics of tacrolimus in adult renal transplant recipients. It has been reported that the cytochrome P450 (CYP) 3A5 genotype is an important cause of variability in tacrolimus pharmacokinetics. However, the predictive performance of population pharmacokinetic (PK) models of tacrolimus should be evaluated prior to their implementation in clinical practice. The aim of the study reported here was to test the predictive performance of these published PK models of tacrolimus. METHODS A literature search of the PubMed and Web of Science databases ultimately led to the inclusion of eight one-compartment models in our analysis. We collected a total of 1715 trough concentrations from 174 patients. Predictive performance was assessed based on visual and numerical comparison bias and imprecision and by the use of simulation-based diagnostics and Bayesian forecasting. RESULTS Of the eight one-compartment models assessed, seven showed better predictive performance in CYP3A5 extensive metabolizers in terms of bias and imprecision. Results of the simulation-based diagnostics also supported the findings. The model based on a Chinese population in 2013 (model 3) showed the best and most stable predictive performance in all the tests and was more informative in CYP3A5 extensive metabolizers. As expected, Bayesian forecasting improved model predictability. Diversity among models and between different CYP3A5 genotypes of the same model was also narrowed by Bayesian forecasting. CONCLUSIONS Based on our results, we recommend using model 3 in CYP3A5 extensive metabolizers in clinical practice. All models had a poor predictive performance in CYP3A5 poor metabolizers, and they should be used with caution in this patient population. However, Bayesian forecasting improved the predictability and reduced differences, and thus the models could be applied in this latter patient population for the design of maintenance dose.
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Affiliation(s)
- Can Hu
- Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, People's Republic of China
| | - Wen-Jun Yin
- Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, People's Republic of China
| | - Dai-Yang Li
- Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, People's Republic of China
| | - Jun-Jie Ding
- Department of Pharmacy, Children's Hospital of Fudan University, Shanghai, 100029, People's Republic of China
| | - Ling-Yun Zhou
- Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, People's Republic of China
| | - Jiang-Lin Wang
- Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, People's Republic of China
| | - Rong-Rong Ma
- Department of Pharmacy, First Affiliated Hospital of Xinjiang Medical University, No. 137 Liyushan South Road, Urumqi, 830054, Xinjiang, People's Republic of China
| | - Kun Liu
- Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, People's Republic of China
| | - Ge Zhou
- Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, People's Republic of China
| | - Xiao-Cong Zuo
- Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, People's Republic of China.
- Center of Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, 410013, People's Republic of China.
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Lancia P, Aurich B, Ha P, Maisin A, Baudouin V, Jacqz-Aigrain E. Adverse Events under Tacrolimus and Cyclosporine in the First 3 Years Post-Renal Transplantation in Children. Clin Drug Investig 2018; 38:157-171. [PMID: 29236209 DOI: 10.1007/s40261-017-0594-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Progress in immunosuppression has reduced acute rejection, graft loss and mortality after renal transplantation. Adverse drug reactions are well described in adults but few data are available in children. Our objectives were to analyse the adverse events reported in the first 3 years post-transplantation in children receiving tacrolimus or cyclosporine-based immunosuppression and compare them with the information of the Summary of Product Characteristics. METHODS This retrospective study included all children who underwent a renal transplant at Hospital Robert Debré between 2002 and 2015. Initial immunosuppression was based on induction, calcineurin inhibitor, mycophenolate mofetil and corticosteroids. Adverse events were collected from medical records and coded using the Medical Dictionary for Regulatory Activities and the implications of tacrolimus and cyclosporine analysed. Statistical analyses were performed using SAS 9.4. RESULTS One hundred and twenty-five children were included. During the observation period [2.7 years (0.6-4.3)], 105 patients received tacrolimus and 39 received cyclosporine. The incidence rate for gastrointestinal disorders was 0.128 and 0.056 by patient-years of exposure (p < 0.05), under tacrolimus and cyclosporine schedules. For neutropenia, it was 0.064 and 0.014 (p < 0.05). The frequencies of toxic nephropathy and gastrointestinal pain were higher than those in the Summary of Product Characteristics of tacrolimus (> 20%) and cyclosporine (> 10%). Cosmetic events for cyclosporine and neutropenia for tacrolimus were frequently observed (18 and 14.3%, respectively), although uncommon in the Summary of Product Characteristics. CONCLUSIONS The exposure-adjusted incidence rate of gastrointestinal disorders and neutropenia was higher in children under the tacrolimus schedule. Our findings contribute to the evaluation of the benefit-risk balance of immunosuppressive therapy following paediatric renal transplantation.
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Affiliation(s)
- Pauline Lancia
- Department of Paediatric Pharmacology and Pharmacogenetics, Hospital Robert Debré, APHP, 48 Boulevard Sérurier, 75019, Paris, France
| | - Beate Aurich
- Department of Paediatric Pharmacology and Pharmacogenetics, Hospital Robert Debré, APHP, 48 Boulevard Sérurier, 75019, Paris, France
| | - Phuong Ha
- Department of Paediatric Pharmacology and Pharmacogenetics, Hospital Robert Debré, APHP, 48 Boulevard Sérurier, 75019, Paris, France
| | - Anne Maisin
- Department of Paediatric Nephrology, Hospital Robert Debré, APHP, 48 Boulevard Sérurier, 75019, Paris, France
| | - Véronique Baudouin
- Department of Paediatric Nephrology, Hospital Robert Debré, APHP, 48 Boulevard Sérurier, 75019, Paris, France
| | - Evelyne Jacqz-Aigrain
- Department of Paediatric Pharmacology and Pharmacogenetics, Hospital Robert Debré, APHP, 48 Boulevard Sérurier, 75019, Paris, France. .,Clinical Investigation Center CIC1426, INSERM, Paris, France. .,Paris Diderot University, Sorbonne Paris Cité, Paris, France.
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Azathioprine to mycophenolate mofetil transition and risk of squamous cell carcinoma after lung transplantation. J Heart Lung Transplant 2018; 37:853-859. [DOI: 10.1016/j.healun.2018.03.012] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2017] [Revised: 02/15/2018] [Accepted: 03/14/2018] [Indexed: 01/08/2023] Open
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Early Steroid Withdrawal Compared With Standard Immunosuppression in Kidney Transplantation - Interim Analysis of the Amsterdam-Leiden-Groningen Randomized Controlled Trial. Transplant Direct 2018; 4:e354. [PMID: 30123827 PMCID: PMC6089519 DOI: 10.1097/txd.0000000000000794] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Accepted: 02/02/2018] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND The optimal immunosuppressive regimen in kidney transplant recipients, delivering maximum efficacy with minimal toxicity, is unknown. METHODS The Amsterdam, LEiden, GROningen trial is a randomized, multicenter, investigator-driven, noninferiority, open-label trial in 305 kidney transplant recipients, in which 2 immunosuppression minimization strategies—one consisting of early steroid withdrawal, the other of tacrolimus minimization 6 months after transplantation—were compared with standard immunosuppression with basiliximab, corticosteroids, tacrolimus, and mycophenolic acid. The primary endpoint was kidney function. Secondary endpoints included death, primary nonfunction, graft failure, rejection, discontinuation of study medication, and a combined endpoint of treatment failure. An interim analysis was scheduled at 6 months, that is, just before tacrolimus minimization. RESULTS This interim analysis revealed no significant differences in Modification of Diet in Renal Disease between the early steroid withdrawal group and the standard immunosuppression groups (43.2 mL/min per 1.73 m2 vs 45.0 mL/min per 1.73 m2, P = 0.408). There were also no significant differences in the secondary endpoints of death (1.0% vs 1.5%; P = 0.737), primary nonfunction (4.1% vs 1.5%, P = 0.159), graft failure (3.1% vs 1.5%, P = 0.370), rejection (18.6% vs 13.6%, P = 0.289), and discontinuation of study medication (19.6% vs 12.6%, P = 0.348). Treatment failure, defined as a composite endpoint of these individual secondary endpoints, was more common in the early steroid withdrawal group (P = 0.027), but this group had fewer serious adverse events and a more favorable cardiovascular risk profile. CONCLUSIONS Based on these interim results, early steroid withdrawal is a safe short-term immunosuppressive strategy. Long-term outcomes, including a comparison with tacrolimus minimization after 6 months, will be reported in the final 2-year analysis.
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Chen L, Prasad GVR. CYP3A5 polymorphisms in renal transplant recipients: influence on tacrolimus treatment. PHARMACOGENOMICS & PERSONALIZED MEDICINE 2018; 11:23-33. [PMID: 29563827 PMCID: PMC5846312 DOI: 10.2147/pgpm.s107710] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Tacrolimus is a commonly used immunosuppressant after kidney transplantation. It has a narrow therapeutic range and demonstrates wide interindividual variability in pharmacokinetics, leading to potential underimmunosuppression or toxicity. Genetic polymorphism in CYP3A5 enzyme expression contributes to differences in tacrolimus bioavailability between individuals. Individuals carrying one or more copies of the wild-type allele *1 express CYP3A5, which increases tacrolimus clearance. CYP3A5 expressers require 1.5 to 2-fold higher tacrolimus doses compared to usual dosing to achieve therapeutic blood concentrations. Individuals with homozygous *3/*3 genotype are CYP3A5 nonexpressers. CYP3A5 nonexpression is the most frequent phenotype in most ethnic populations, except blacks. Differences between CYP3A5 genotypes in tacrolimus disposition have not translated into differences in clinical outcomes, such as acute rejection and graft survival. Therefore, although genotype-based dosing may improve achievement of therapeutic drug concentrations with empiric dosing, its role in clinical practice is unclear. CYP3A5 genotype may predict differences in absorption of extended-release and immediate-release oral formulations of tacrolimus. Two studies found that CYP3A5 expressers require higher doses of tacrolimus in the extended-release formulation compared to immediate release. CYP3A5 genotype plays a role in determining the impact of interacting drugs, such as fluconazole, on tacrolimus pharmacokinetics. Evidence conflicts regarding the impact of CYP3A5 genotype on risk of nephrotoxicity associated with tacrolimus. Further study is required.
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Affiliation(s)
- Lucy Chen
- Kidney Transplant Program, St Michael's Hospital, Toronto, ON, Canada
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Jones-Hughes T, Snowsill T, Haasova M, Coelho H, Crathorne L, Cooper C, Mujica-Mota R, Peters J, Varley-Campbell J, Huxley N, Moore J, Allwood M, Lowe J, Hyde C, Hoyle M, Bond M, Anderson R. Immunosuppressive therapy for kidney transplantation in adults: a systematic review and economic model. Health Technol Assess 2018; 20:1-594. [PMID: 27578428 DOI: 10.3310/hta20620] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND End-stage renal disease is a long-term irreversible decline in kidney function requiring renal replacement therapy: kidney transplantation, haemodialysis or peritoneal dialysis. The preferred option is kidney transplantation, followed by immunosuppressive therapy (induction and maintenance therapy) to reduce the risk of kidney rejection and prolong graft survival. OBJECTIVES To review and update the evidence for the clinical effectiveness and cost-effectiveness of basiliximab (BAS) (Simulect(®), Novartis Pharmaceuticals UK Ltd) and rabbit anti-human thymocyte immunoglobulin (rATG) (Thymoglobulin(®), Sanofi) as induction therapy, and immediate-release tacrolimus (TAC) (Adoport(®), Sandoz; Capexion(®), Mylan; Modigraf(®), Astellas Pharma; Perixis(®), Accord Healthcare; Prograf(®), Astellas Pharma; Tacni(®), Teva; Vivadex(®), Dexcel Pharma), prolonged-release tacrolimus (Advagraf(®) Astellas Pharma), belatacept (BEL) (Nulojix(®), Bristol-Myers Squibb), mycophenolate mofetil (MMF) (Arzip(®), Zentiva; CellCept(®), Roche Products; Myfenax(®), Teva), mycophenolate sodium (MPS) (Myfortic(®), Novartis Pharmaceuticals UK Ltd), sirolimus (SRL) (Rapamune(®), Pfizer) and everolimus (EVL) (Certican(®), Novartis) as maintenance therapy in adult renal transplantation. METHODS Clinical effectiveness searches were conducted until 18 November 2014 in MEDLINE (via Ovid), EMBASE (via Ovid), Cochrane Central Register of Controlled Trials (via Wiley Online Library) and Web of Science (via ISI), Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects and Health Technology Assessment (The Cochrane Library via Wiley Online Library) and Health Management Information Consortium (via Ovid). Cost-effectiveness searches were conducted until 18 November 2014 using a costs or economic literature search filter in MEDLINE (via Ovid), EMBASE (via Ovid), NHS Economic Evaluation Database (via Wiley Online Library), Web of Science (via ISI), Health Economic Evaluations Database (via Wiley Online Library) and the American Economic Association's electronic bibliography (via EconLit, EBSCOhost). Included studies were selected according to predefined methods and criteria. A random-effects model was used to analyse clinical effectiveness data (odds ratios for binary data and mean differences for continuous data). Network meta-analyses were undertaken within a Bayesian framework. A new discrete time-state transition economic model (semi-Markov) was developed, with acute rejection, graft function (GRF) and new-onset diabetes mellitus used to extrapolate graft survival. Recipients were assumed to be in one of three health states: functioning graft, graft loss or death. RESULTS Eighty-nine randomised controlled trials (RCTs), of variable quality, were included. For induction therapy, no treatment appeared more effective than another in reducing graft loss or mortality. Compared with placebo/no induction, rATG and BAS appeared more effective in reducing biopsy-proven acute rejection (BPAR) and BAS appeared more effective at improving GRF. For maintenance therapy, no treatment was better for all outcomes and no treatment appeared most effective at reducing graft loss. BEL + MMF appeared more effective than TAC + MMF and SRL + MMF at reducing mortality. MMF + CSA (ciclosporin), TAC + MMF, SRL + TAC, TAC + AZA (azathioprine) and EVL + CSA appeared more effective than CSA + AZA and EVL + MPS at reducing BPAR. SRL + AZA, TAC + AZA, TAC + MMF and BEL + MMF appeared to improve GRF compared with CSA + AZA and MMF + CSA. In the base-case deterministic and probabilistic analyses, BAS, MMF and TAC were predicted to be cost-effective at £20,000 and £30,000 per quality-adjusted life-year (QALY). When comparing all regimens, only BAS + TAC + MMF was cost-effective at £20,000 and £30,000 per QALY. LIMITATIONS For included trials, there was substantial methodological heterogeneity, few trials reported follow-up beyond 1 year, and there were insufficient data to perform subgroup analysis. Treatment discontinuation and switching were not modelled. FUTURE WORK High-quality, better-reported, longer-term RCTs are needed. Ideally, these would be sufficiently powered for subgroup analysis and include health-related quality of life as an outcome. CONCLUSION Only a regimen of BAS induction followed by maintenance with TAC and MMF is likely to be cost-effective at £20,000-30,000 per QALY. STUDY REGISTRATION This study is registered as PROSPERO CRD42014013189. FUNDING The National Institute for Health Research Health Technology Assessment programme.
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Affiliation(s)
- Tracey Jones-Hughes
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Tristan Snowsill
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Marcela Haasova
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Helen Coelho
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Louise Crathorne
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Chris Cooper
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Ruben Mujica-Mota
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Jaime Peters
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Jo Varley-Campbell
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Nicola Huxley
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Jason Moore
- Exeter Kidney Unit, Royal Devon and Exeter Foundation Trust Hospital, Exeter, UK
| | - Matt Allwood
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Jenny Lowe
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Chris Hyde
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Martin Hoyle
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Mary Bond
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
| | - Rob Anderson
- Peninsula Technology Assessment Group (PenTAG), University of Exeter, Exeter, UK
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Haasova M, Snowsill T, Jones-Hughes T, Crathorne L, Cooper C, Varley-Campbell J, Mujica-Mota R, Coelho H, Huxley N, Lowe J, Dudley J, Marks S, Hyde C, Bond M, Anderson R. Immunosuppressive therapy for kidney transplantation in children and adolescents: systematic review and economic evaluation. Health Technol Assess 2018; 20:1-324. [PMID: 27557331 DOI: 10.3310/hta20610] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND End-stage renal disease is a long-term irreversible decline in kidney function requiring kidney transplantation, haemodialysis or peritoneal dialysis. The preferred option is kidney transplantation followed by induction and maintenance immunosuppressive therapy to reduce the risk of kidney rejection and prolong graft survival. OBJECTIVES To systematically review and update the evidence for the clinical effectiveness and cost-effectiveness of basiliximab (BAS) (Simulect,(®) Novartis Pharmaceuticals) and rabbit antihuman thymocyte immunoglobulin (Thymoglobuline,(®) Sanofi) as induction therapy and immediate-release tacrolimus [Adoport(®) (Sandoz); Capexion(®) (Mylan); Modigraf(®) (Astellas Pharma); Perixis(®) (Accord Healthcare); Prograf(®) (Astellas Pharma); Tacni(®) (Teva); Vivadex(®) (Dexcel Pharma)], prolonged-release tacrolimus (Advagraf,(®) Astellas Pharma); belatacept (BEL) (Nulojix,(®) Bristol-Myers Squibb), mycophenolate mofetil (MMF) [Arzip(®) (Zentiva), CellCept(®) (Roche Products), Myfenax(®) (Teva), generic MMF is manufactured by Accord Healthcare, Actavis, Arrow Pharmaceuticals, Dr Reddy's Laboratories, Mylan, Sandoz and Wockhardt], mycophenolate sodium, sirolimus (Rapamune,(®) Pfizer) and everolimus (Certican,(®) Novartis Pharmaceuticals) as maintenance therapy in children and adolescents undergoing renal transplantation. DATA SOURCES Clinical effectiveness searches were conducted to 7 January 2015 in MEDLINE (via Ovid), EMBASE (via Ovid), Cochrane Central Register of Controlled Trials (via Wiley Online Library) and Web of Science [via Institute for Scientific Information (ISI)], Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects and Health Technology Assessment (HTA) (The Cochrane Library via Wiley Online Library) and Health Management Information Consortium (via Ovid). Cost-effectiveness searches were conducted to 15 January 2015 using a costs or economic literature search filter in MEDLINE (via Ovid), EMBASE (via Ovid), NHS Economic Evaluation Databases (via Wiley Online Library), Web of Science (via ISI), Health Economic Evaluations Database (via Wiley Online Library) and EconLit (via EBSCOhost). REVIEW METHODS Titles and abstracts were screened according to predefined inclusion criteria, as were full texts of identified studies. Included studies were extracted and quality appraised. Data were meta-analysed when appropriate. A new discrete time state transition economic model (semi-Markov) was developed; graft function, and incidences of acute rejection and new-onset diabetes mellitus were used to extrapolate graft survival. Recipients were assumed to be in one of three health states: functioning graft, graft loss or death. RESULTS Three randomised controlled trials (RCTs) and four non-RCTs were included. The RCTs only evaluated BAS and tacrolimus (TAC). No statistically significant differences in key outcomes were found between BAS and placebo/no induction. Statistically significantly higher graft function (p < 0.01) and less biopsy-proven acute rejection (odds ratio 0.29, 95% confidence interval 0.15 to 0.57) was found between TAC and ciclosporin (CSA). Only one cost-effectiveness study was identified, which informed NICE guidance TA99. BAS [with TAC and azathioprine (AZA)] was predicted to be cost-effective at £20,000-30,000 per quality-adjusted life year (QALY) versus no induction (BAS was dominant). BAS (with CSA and MMF) was not predicted to be cost-effective at £20,000-30,000 per QALY versus no induction (BAS was dominated). TAC (with AZA) was predicted to be cost-effective at £20,000-30,000 per QALY versus CSA (TAC was dominant). A model based on adult evidence suggests that at a cost-effectiveness threshold of £20,000-30,000 per QALY, BAS and TAC are cost-effective in all considered combinations; MMF was also cost-effective with CSA but not TAC. LIMITATIONS The RCT evidence is very limited; analyses comparing all interventions need to rely on adult evidence. CONCLUSIONS TAC is likely to be cost-effective (vs. CSA, in combination with AZA) at £20,000-30,000 per QALY. Analysis based on one RCT found BAS to be dominant, but analysis based on another RCT found BAS to be dominated. BAS plus TAC and AZA was predicted to be cost-effective at £20,000-30,000 per QALY when all regimens were compared using extrapolated adult evidence. High-quality primary effectiveness research is needed. The UK Renal Registry could form the basis for a prospective primary study. STUDY REGISTRATION This study is registered as PROSPERO CRD42014013544. FUNDING The National Institute for Health Research HTA programme.
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Affiliation(s)
- Marcela Haasova
- Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK
| | - Tristan Snowsill
- Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK
| | - Tracey Jones-Hughes
- Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK
| | - Louise Crathorne
- Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK
| | - Chris Cooper
- Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK
| | - Jo Varley-Campbell
- Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK
| | - Ruben Mujica-Mota
- Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK
| | - Helen Coelho
- Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK
| | - Nicola Huxley
- Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK
| | - Jenny Lowe
- Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK
| | - Jan Dudley
- Department of Paediatric Nephrology, Bristol Royal Hospital for Children (University Hospitals Bristol NHS Foundation Trust), Bristol, UK
| | - Stephen Marks
- Department of Paediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Chris Hyde
- Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK
| | - Mary Bond
- Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK
| | - Rob Anderson
- Peninsula Technology Assessment Group (PenTAG), Evidence Synthesis & Modelling for Health Improvement, University of Exeter, Exeter, UK
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Vesole AS, Nagahama Y, Granner MA, Howard MA, Kawasaki H, Dlouhy BJ. Drug-resistant epilepsy development following stem cell transplant and cyclosporine neurotoxicity induced seizures: Case report in an adult and analysis of reported cases in the literature. EPILEPSY & BEHAVIOR CASE REPORTS 2018; 10:8-13. [PMID: 30062084 PMCID: PMC6064196 DOI: 10.1016/j.ebcr.2018.01.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/07/2018] [Revised: 01/19/2018] [Accepted: 01/27/2018] [Indexed: 11/22/2022]
Abstract
Introduction Drug-resistant epilepsy (DRE) occurs in 20–30% of all patients who develop epilepsy and can occur from diverse causes. Cyclosporine-A (CSA) is an immunosuppressive drug utilized to prevent graft-versus-host disease (GvHD) in transplant patients and is known to cause neurotoxicity, including seizures. In some cases, however, patients can develop DRE. Only a limited number of cases have been reported in which DRE has developed after CSA exposure — all in children. Here we present a rare case of an adult developing DRE after post-transplant CSA neurotoxicity. In addition, we provide a comprehensive review and analysis of all reported cases in the literature. Case report A 29-year-old man with Non-Hodgkin's Lymphoma underwent an allogenic hematopoietic stem cell transplant and experienced a CSA-induced seizure at 7.5 months' post-transplant. The patient was discontinued on CSA and began a low dose tacrolimus regimen. At 33 months' post-transplant, he had seizure recurrence and developed DRE. Imaging revealed right mesial temporal sclerosis (MTS) and video EEG localized ictal activity to the right anterior temporal lobe. He was successfully treated with a right anterior temporal lobectomy and amygdalohippocampectomy. Literature review Seven peer-reviewed studies described 15 patients who underwent transplantation with post-transplant CSA administration and subsequently developed DRE following an initial CSA-induced seizure. All 15 patients were children suggesting that young age is a risk factor for DRE after CSA-induced seizures. Initial CSA-induced seizures occurred at an average of 1.6 ± 1.1 months after transplant and seizure recurrence 9.2 ± 8.0 months after transplant. All reported CSA routes of administration (n = 6) were intravenous and 7 of 9 (78%) reported CSA blood levels above the therapeutic range. The incidence of MTS (40%) in these 15 patients was significantly higher than the incidence in the general DRE population (24%) and was most effectively treated via epilepsy surgery. Conclusions The use of cyclosporine for GvHD prophylaxis and treatment following transplantation may cause seizures and be associated with DRE. Although discontinuation and dose decrease of CSA often reverse adverse neurological events, initial CSA-induced seizures may be associated with MTS that and subsequent greater risk of DRE development.
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Affiliation(s)
- Adam S Vesole
- University of Iowa Carver College of Medicine, Iowa City, IA, USA
| | - Yasunori Nagahama
- Department of Neurosurgery, University of Iowa Hospitals and Clinics, Iowa City, IA, USA
| | - Mark A Granner
- Department of Neurology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA
| | - Matthew A Howard
- University of Iowa Carver College of Medicine, Iowa City, IA, USA.,Department of Neurosurgery, University of Iowa Hospitals and Clinics, Iowa City, IA, USA.,Pappajohn Biomedical Institute, University of Iowa Carver College of Medicine, Iowa City, IA, USA
| | - Hiroto Kawasaki
- Department of Neurosurgery, University of Iowa Hospitals and Clinics, Iowa City, IA, USA
| | - Brian J Dlouhy
- University of Iowa Carver College of Medicine, Iowa City, IA, USA.,Department of Neurosurgery, University of Iowa Hospitals and Clinics, Iowa City, IA, USA.,Pappajohn Biomedical Institute, University of Iowa Carver College of Medicine, Iowa City, IA, USA
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Correlation between disease activity and serum ferritin in clinically amyopathic dermatomyositis with rapidly-progressive interstitial lung disease: a case report. BMC Res Notes 2018; 11:34. [PMID: 29338781 PMCID: PMC5770999 DOI: 10.1186/s13104-018-3146-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2017] [Accepted: 01/09/2018] [Indexed: 01/07/2023] Open
Abstract
Background Clinically amyopathic dermatomyositis with anti-Melanoma Differentiation-Associated gene 5 (MDA5) antibody often presents with severe interstitial lung disease. Although serum ferritin level is known to reflect interstitial lung disease activity, there are few case reports describing this association. Case presentation A 58-year-old man was referred to our outpatient clinic with a 3-week history of cough and respiratory distress. He had erythema over the V area of the neck and a Gottron’s sign. Chest computed tomography revealed diffuse ground-glass opacities and reticular shadows in both lungs. Test for anti-MDA5 antibody was positive. After admission, he received triple combination therapy (methylprednisolone pulse therapy, tacrolimus, and cyclophosphamide). However, his respiratory condition worsened as the serum ferritin level increased. Despite no apparent deterioration on chest radiography, he ultimately died due to respiratory failure. Conclusions In this case, triple combination therapy was not effective for the patient’s respiratory condition. The serum ferritin level was correlated with disease activity and was more useful than chest radiography for monitoring clinical status.
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Belatacept Compared With Tacrolimus for Kidney Transplantation: A Propensity Score Matched Cohort Study. Transplantation 2017; 101:2582-2589. [PMID: 27941427 DOI: 10.1097/tp.0000000000001589] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
BACKGROUND Although tacrolimus is the basis of most maintenance immunosuppression regimens for kidney transplantation, concerns about toxicity have made alternative agents, such as belatacept, attractive to clinicians. However, limited data exist to directly compare outcomes with belatacept-based regimens to tacrolimus. METHODS We performed a propensity score matched cohort study of adult kidney transplant recipients transplanted between May 1, 2001, and December 31, 2015, using national transplant registry data to compare patient and allograft survival in patients discharged from their index hospitalization on belatacept-based versus tacrolimus-based regimens. RESULTS In the primary analysis, we found that belatacept was not associated with a statistically significant difference in risk of patient death (hazard ratio, 0.84; 95% confidence interval [CI], 0.61-1.15, P = 0.28) or allograft loss (hazard ratio, 0.83; 95% CI, 0.62-1.11; P = 0.20) despite an increased risk of acute rejection in the first year posttransplant (odds ratio, 3.12; 95% CI, 2.13-4.57; P < 0.001). These findings were confirmed in additional sensitivity analyses that accounted for use of belatacept in combination with tacrolimus, transplant center effects, and differing approaches to matching. CONCLUSIONS Belatacept appears to have similar longitudinal risk of mortality and allograft failure compared with tacrolimus-based regimens. These data are encouraging but require confirmation in prospective randomized controlled trials.
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Würdinger M, Modrow S, Plentz A. Impact of Parvovirus B19 Viremia in Liver Transplanted Children on Anemia: A Retrospective Study. Viruses 2017; 9:v9060149. [PMID: 28608818 PMCID: PMC5490825 DOI: 10.3390/v9060149] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Revised: 05/30/2017] [Accepted: 06/06/2017] [Indexed: 12/18/2022] Open
Abstract
Acute parvovirus B19 (B19V) infection in immunocompromised patients may lead to severe anemia. However, in adult transplant recipients, B19V reactivations without anemia and low-level viremia are common. The impact of B19V in pediatric transplant patients, with high risk of primary infection, is investigated here. In a six-month period, 159 blood samples of 54 pediatric liver transplant recipients were tested for B19V DNA by quantitative real-time PCR. Viremia was correlated with anemia and immunosuppression and compared with rates in adult transplant recipients. B19V DNA was detected in 5/54 patients. Primary B19V infections were observed in four patients prior to and in one patient after transplantation. Rates of viremia were significantly higher in pediatric recipients than in adults. Prolonged virus shedding after primary infection prior to transplantation accounts for most viremic cases. Anemia was significantly more frequent in samples from viremic patients, but remained mild. In 15% of anemic samples, B19V DNA was detected. Therefore, in anemic pediatric transplant recipients, diagnostics for B19V seem reasonable.
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Affiliation(s)
- Michael Würdinger
- Institute of Medical Microbiology and Hygiene, University of Regensburg, 93053 Regensburg, Germany.
- Department of Surgery and Transplantation, University Hospital of Zurich, 8091 Zürich, Switzerland.
| | - Susanne Modrow
- Institute of Medical Microbiology and Hygiene, University of Regensburg, 93053 Regensburg, Germany.
| | - Annelie Plentz
- Institute of Medical Microbiology and Hygiene, University of Regensburg, 93053 Regensburg, Germany.
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Kizilbash SJ, Rheault MN, Bangdiwala A, Matas A, Chinnakotla S, Chavers BM. Infection rates in tacrolimus versus cyclosporine-treated pediatric kidney transplant recipients on a rapid discontinuation of prednisone protocol: 1-year analysis. Pediatr Transplant 2017; 21:10.1111/petr.12919. [PMID: 28371243 PMCID: PMC5423828 DOI: 10.1111/petr.12919] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/17/2017] [Indexed: 12/16/2022]
Abstract
AR is lower in pKTx recipients on Tac vs CsA. Data comparing infection outcomes for children treated with these agents are limited. We retrospectively studied infection outcomes in 96 pKTx recipients on a RDP. PS, DCGS, AR, and infection-free survival were assessed using Kaplan-Meier/log-rank tests and proportional hazards models. There were no differences in 1-year PS, DCGS, or AR between Tac and CsA recipients. After adjusting for AR, the hazard of CMV viremia was 4.0 times higher (95%CI: 1.04, 15.5; P = .044) and that of BK viremia was 3.8 times higher (95%CI: 1.5, 10.2; P = .007) in Tac recipients. The incidence of EBV viremia was similar between the groups (P = .56). PostTx lymphoproliferative disease was only observed in Tac recipients (3%). There was no difference in the incidence of pneumonia, urinary tract, or Clostridium difficile infections between Tac and CsA recipients. Among KTx recipients on RDP, the hazards of CMV and BK viremia within 1 year post-KTx were significantly higher in Tac recipients compared to CsA. Regular assessment for infections and lower Tac trough levels may be warranted in Tac recipients.
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Affiliation(s)
- Sarah J Kizilbash
- Department of Pediatric Nephrology, University of Minnesota, Minneapolis, MN, United States
| | - Michelle N Rheault
- Department of Pediatric Nephrology, University of Minnesota, Minneapolis, MN, United States
| | - Ananta Bangdiwala
- Biostatistics and Bioinformatics Core, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, United States
| | - Arthur Matas
- Department of Transplant Surgery, University of Minnesota, Minneapolis, MN, United States
| | - Srinath Chinnakotla
- Department of Transplant Surgery, University of Minnesota, Minneapolis, MN, United States
| | - Blanche M Chavers
- Department of Pediatric Nephrology, University of Minnesota, Minneapolis, MN, United States
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Abstract
Major neurologic morbidity, such as seizures and encephalopathy, complicates 20-30% of organ and stem cell transplantation procedures. The majority of these disorders occur in the early posttransplant period, but recipients remain at risk for opportunistic infections and other nervous system disorders for many years. These long-term risks may be increasing as acute survival increases, and a greater number of "sicker" patients are exposed to long-term immunosuppression. Drug neurotoxicity accounts for a significant proportion of complications, with posterior reversible leukoencephalopathy syndrome, primarily associated with calcineurin inhibitors (i.e., cyclosporine and tacrolimus), being prominent as a cause of seizures and neurologic deficits. A thorough evaluation of any patient who develops neurologic symptoms after transplantation is mandatory, since reversible and treatable conditions could be found, and important prognostic information can be obtained.
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Affiliation(s)
- R Dhar
- Division of Neurocritical Care, Department of Neurology, Washington University, St. Louis, MO, USA.
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Hellemans R, Bosmans J, Abramowicz D. Induction Therapy for Kidney Transplant Recipients: Do We Still Need Anti-IL2 Receptor Monoclonal Antibodies? Am J Transplant 2017; 17:22-27. [PMID: 27223882 PMCID: PMC5215533 DOI: 10.1111/ajt.13884] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2015] [Revised: 05/19/2016] [Accepted: 05/19/2016] [Indexed: 01/25/2023]
Abstract
Induction therapy with antilymphocyte biological agents is widely used after kidney transplantation, most commonly T lymphocyte-depleting rabbit-derived antithymocyte globulin (rATG) or an IL-2 receptor antagonist (IL2RA). Early randomized trials showed that rATG or IL2RA induction reduces early acute rejection, prompting recommendations by Kidney Disease Improving Global Outcomes that IL2RA induction be used routinely in first-line therapy after kidney transplantation, with lymphocyte-depleting induction reserved for high-risk cases. These studies, however, mainly used outdated maintenance regimens. No large randomized trial has examined the effect of IL2RA or rATG induction versus no induction in patients receiving tacrolimus, mycophenolic acid and steroids. With this triple maintenance therapy, the addition of induction may achieve an absolute risk reduction for acute rejection of only 1-4% in standard-risk patients without improving graft or patient survival. In contrast, rATG induction lowers the relative risk of acute rejection by almost 50% versus IL2RA in patients with high immunological risk. These recent data raise questions about the need for IL2RA in kidney transplantation, as it may no longer be beneficial in standard-risk transplantation and may be inferior to rATG in high-risk situations. Updated evidence-based guidelines are necessary to support clinicians deciding whether and what induction therapy is required for their transplant patients today.
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Affiliation(s)
- R. Hellemans
- Dienst NefrologieUniversitair Ziekenhuis AntwerpenEdegemBelgium
| | - J.‐L. Bosmans
- Dienst NefrologieUniversitair Ziekenhuis AntwerpenEdegemBelgium
| | - D. Abramowicz
- Dienst NefrologieUniversitair Ziekenhuis AntwerpenEdegemBelgium
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Siemens W, Xander C, Meerpohl JJ, Buroh S, Antes G, Schwarzer G, Becker G, Cochrane Pain, Palliative and Supportive Care Group. Pharmacological interventions for pruritus in adult palliative care patients. Cochrane Database Syst Rev 2016; 11:CD008320. [PMID: 27849111 PMCID: PMC6734122 DOI: 10.1002/14651858.cd008320.pub3] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND This is an update of the original Cochrane review published in 2013 (Issue 6). Pruritus occurs in patients with disparate underlying diseases and is caused by different pathologic mechanisms. In palliative care patients, pruritus is not the most prevalent but is one of the most puzzling symptoms. It can cause considerable discomfort and affects patients' quality of life. OBJECTIVES To assess the effects of different pharmacological treatments for preventing or treating pruritus in adult palliative care patients. SEARCH METHODS For this update, we searched CENTRAL (the Cochrane Library), and MEDLINE (OVID) up to 9 June 2016 and Embase (OVID) up to 7 June 2016. In addition, we searched trial registries and checked the reference lists of all relevant studies, key textbooks, reviews and websites, and we contacted investigators and specialists in pruritus and palliative care regarding unpublished data. SELECTION CRITERIA We included randomised controlled trials (RCTs) assessing the effects of different pharmacological treatments, compared with a placebo, no treatment, or an alternative treatment, for preventing or treating pruritus in palliative care patients. DATA COLLECTION AND ANALYSIS Two review authors independently assessed the identified titles and abstracts, performed data extraction and assessed the risk of bias and methodological quality. We summarised the results descriptively and quantitatively (meta-analyses) according to the different pharmacological interventions and the diseases associated with pruritus. We assessed the evidence using GRADE (Grading of Recommendations Assessment, Development and Evaluation) and created 10 'Summary of findings' tables. MAIN RESULTS In total, we included 50 studies and 1916 participants in the review. We added 10 studies with 627 participants for this update. Altogether, we included 39 different treatments for pruritus in four different patient groups.The overall risk of bias profile was heterogeneous and ranged from high to low risk. However, 48 studies (96%) had a high risk of bias due to low sample size (i.e. fewer than 50 participants per treatment arm). Using GRADE criteria, we downgraded our judgement on the quality of evidence to moderate in seven and to low in three comparisons for our primary outcome (pruritus), mainly due to imprecision and risk of bias.In palliative care participants with pruritus of different nature, the treatment with the drug paroxetine, a selective serotonin reuptake inhibitor, reduced pruritus by 0.78 points (numerical analogue scale from 0 to 10; 95% confidence interval (CI) -1.19 to -0.37; one RCT, N = 48, quality of evidence: moderate) compared to placebo.For participants suffering from uraemic pruritus (UP), gabapentin was more effective than placebo (visual analogue scale (VAS): 0 to 10), mean difference (MD) -5.91, 95% CI -6.87 to -4.96; two RCTs, N = 118, quality of evidence: moderate). The κ-opioid receptor agonist nalfurafine showed amelioration of UP (VAS 0 to 10, MD -0.95, 95% CI -1.32 to -0.58; three RCTs, N = 422, quality of evidence: moderate) and only few adverse events. Moreover, cromolyn sodium relieved UP participants from pruritus by 2.94 points on the VAS (0 to 10) (95% CI -4.04 to -1.83; two RCTs, N = 100, quality of evidence: moderate) compared to placebo.In participants with cholestatic pruritus (CP), data favoured rifampin (VAS: 0 to 100, MD -24.64, 95% CI -31.08 to -18.21; two RCTs, N = 42, quality of evidence: low) and flumecinol (RR > 1 favours treatment group; RR 1.89, 95% CI 1.05 to 3.39; two RCTs, N = 69, quality of evidence: low) and showed a low incidence of adverse events in comparison with placebo. The opioid antagonist naltrexone reduced pruritus for participants with CP (VAS: 0 to 10, MD -2.26, 95% CI -3.19 to -1.33; two RCTs, N = 52, quality of evidence: moderate) compared to placebo. However, effects in participants with UP were inconclusive (percentage difference -12.30%, 95% CI -25.82% to 1.22%, one RCT, N = 32). Furthermore, large doses of opioid antagonists (e.g. naltrexone) could be inappropriate in palliative care patients because of the risk of reducing analgesia.For participants with HIV-associated pruritus, it is uncertain whether drug treatment with hydroxyzine hydrochloride, pentoxifylline, triamcinolone or indomethacin reduces pruritus because the evidence was of very low quality (e.g. small sample size, lack of blinding). AUTHORS' CONCLUSIONS Different interventions tended to be effective for CP and UP. However, therapies for patients with malignancies are still lacking. Due to the small sample sizes in most meta-analyses and the heterogeneous methodological quality of the included trials, the results should be interpreted cautiously in terms of generalisability.
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Affiliation(s)
- Waldemar Siemens
- Faculty of Medicine, University of Freiburg, GermanyClinic for Palliative Care, Medical Center ‐ University of FreiburgRobert‐Koch‐Straße 3FreiburgGermany
| | - Carola Xander
- Faculty of Medicine, University of Freiburg, GermanyClinic for Palliative Care, Medical Center ‐ University of FreiburgRobert‐Koch‐Straße 3FreiburgGermany
| | - Joerg J Meerpohl
- Medical Center ‐ University of FreiburgCochrane GermanyBreisacher Straße 153FreiburgGermany79110
| | - Sabine Buroh
- University Medical CenterLibrary of the Center of SurgeryHugstetterstrasse 55FreiburgBaden‐WürttembergGermany79115
| | - Gerd Antes
- Medical Center ‐ University of FreiburgCochrane GermanyBreisacher Straße 153FreiburgGermany79110
| | - Guido Schwarzer
- Medical Center ‐ University of FreiburgCenter for Medical Biometry and Medical InformaticsStefan‐Meier‐Str. 26FreiburgGermanyD‐79104
| | - Gerhild Becker
- Faculty of Medicine, University of Freiburg, GermanyClinic for Palliative Care, Medical Center ‐ University of FreiburgRobert‐Koch‐Straße 3FreiburgGermany
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