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      An Italian multicentre distributed data research network to study the use, effectiveness, and safety of immunosuppressive drugs in transplant patients: Framework and perspectives of the CESIT project

      research-article
      1 , * , , 1 , 1 , 1 , 1 , 2 , 2 , 3 , 3 , 3 , 3 , 3 , 4 , 4 , 4 , 5 , 6 , 7 , 8 , 8 , 8 , 9 , 1 , 1 , CESIT Study Group 10
      Frontiers in Pharmacology
      Frontiers Media S.A.
      immunosuppressive treatment, transplant, research network, distributed analysis, pharmacoepidemiology, pharmaco-utilization, multidisciplinary approach

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          Abstract

          The goal of post-transplant immunosuppressive drug therapy is to prevent organ rejection while minimizing drug toxicities. In clinical practice, a multidrug approach is commonly used and involves drugs with different mechanisms of action, including calcineurin inhibitors (CNI) (tacrolimus or cyclosporine), antimetabolite (antimet) (mycophenolate or azathioprine), inhibitors of mechanistic target of rapamycin (mTOR) (sirolimus or everolimus), and/or steroids. Although evidence based on several randomized clinical trials is available, the optimal immunosuppressive therapy has not been established and may vary among organ transplant settings. To improve the knowledge on this topic, a multiregional research network to Compare the Effectiveness and Safety of Immunosuppressive drugs in Transplant patients (CESIT) has been created with the financial support of the Italian Medicines Agency. In this article, we describe the development of this network, the framework that was designed to perform observational studies, and we also give an overview of the preliminary results that we have obtained. A multi-database transplant cohort was enrolled using a common data model based on healthcare claims data of four Italian regions (Lombardy, Veneto, Lazio, and Sardinia). Analytical datasets were created using an open-source tool for distributed analysis. To link the National Transplant Information System to the regional transplant cohorts, a semi-deterministic record linkage procedure was performed. Overall, 6,914 transplant patients from 2009–19 were identified: 4,029 (58.3%) for kidney, 2,219 (32.1%) for liver, 434 (6.3%) for heart, and 215 (3.1%) for lung. As expected, demographic and clinical characteristics showed considerable variability among organ settings. Although the triple therapy in terms of CNI + antimet/mTOR + steroids was widely dispensed for all settings (63.7% for kidney, 33.5% for liver, 53.3% for heart, and 63.7% for lung), differences in the active agents involved were detected. The CESIT network represents a great opportunity to study several aspects related to the use, safety, and effectiveness of post-transplant maintenance immunosuppressive therapy in real practice.

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          Most cited references32

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          Big data in organ transplantation: registries and administrative claims.

          The field of organ transplantation benefits from large, comprehensive, transplant-specific national data sets available to researchers. In addition to the widely used Organ Procurement and Transplantation Network (OPTN)-based registries (the United Network for Organ Sharing and Scientific Registry of Transplant Recipients data sets) and United States Renal Data System (USRDS) data sets, there are other publicly available national data sets, not specific to transplantation, which have historically been underutilized in the field of transplantation. Of particular interest are the Nationwide Inpatient Sample and State Inpatient Databases, produced by the Agency for Healthcare Research and Quality. The USRDS database provides extensive data relevant to studies of kidney transplantation. Linkage of publicly available data sets to external data sources such as private claims or pharmacy data provides further resources for registry-based research. Although these resources can transcend some limitations of OPTN-based registry data, they come with their own limitations, which must be understood to avoid biased inference. This review discusses different registry-based data sources available in the United States, as well as the proper design and conduct of registry-based research.
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            KDIGO clinical practice guideline for the care of kidney transplant recipients: a summary.

            The 2009 Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline on the monitoring, management, and treatment of kidney transplant recipients is intended to assist the practitioner caring for adults and children after kidney transplantation. The guideline development process followed an evidence-based approach, and management recommendations are based on systematic reviews of relevant treatment trials. Critical appraisal of the quality of the evidence and the strength of recommendations followed the Grades of Recommendation Assessment, Development, and Evaluation (GRADE) approach. The guideline makes recommendations for immunosuppression and graft monitoring, as well as prevention and treatment of infection, cardiovascular disease, malignancy, and other complications that are common in kidney transplant recipients, including hematological and bone disorders. Limitations of the evidence, especially the lack of definitive clinical outcome trials, are discussed and suggestions are provided for future research. This summary includes a brief description of methodology and the complete guideline recommendations but does not include the rationale and references for each recommendation, which are published elsewhere.
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              Tacrolimus versus ciclosporin as primary immunosuppression for kidney transplant recipients: meta-analysis and meta-regression of randomised trial data.

              To compare the positive and negative effects of tacrolimus and ciclosporin as initial treatment for renal transplant recipients. Systematic review. Reports of comparative randomised trials of tacrolimus and ciclosporin identified by searches of Medline, Embase, the Cochrane Register of Controlled Trials, the Cochrane Renal Group Specialist Register, and conference proceedings. Two reviewers assessed trials for eligibility and quality and extracted data independently. Data were synthesised (random effects model) and results expressed as relative risk (RR), with values < 1 favouring tacrolimus. Subgroup analysis and meta-regression were used to examine potential effect modification by differences in trial design and immunosuppressive co-interventions. 123 reports from 30 trials (4102 patients) were included. At six months, graft loss was significantly reduced in tacrolimus treated recipients (RR = 0.56, 95% confidence interval 0.36 to 0.86), and this effect persisted up to three years. The relative reduction in graft loss with tacrolimus diminished with higher concentrations of tacrolimus (P = 0.04) but did not vary with ciclosporin formulation (P = 0.97) or ciclosporin concentration (P = 0.38). At one year, tacrolimus treated patients had less acute rejection (RR = 0.69, 0.60 to 0.79) and less steroid resistant rejection (RR = 0.49, 0.37 to 0.64) but more diabetes mellitus requiring insulin (RR = 1.86, 1.11 to 3.09), tremor, headache, diarrhoea, dyspepsia, and vomiting. The relative excess of diabetes increased with higher concentrations of tacrolimus (P = 0.003). Ciclosporin treated recipients had significantly more constipation and cosmetic side effects. No differences were seen in infection or malignancy. Treating 100 recipients with tacrolimus instead of ciclosporin for the first year after transplantation avoids 12 patients having acute rejection and two losing their graft but causes an extra five patients to develop insulin dependent diabetes. Optimal drug choice may vary between patients.
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                Author and article information

                Contributors
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                15 September 2022
                2022
                : 13
                : 959267
                Affiliations
                [1] 1 Department of Epidemiology , Lazio Regional Health Service , Rome, Italy
                [2] 2 National Center for Drug Research and Evaluation , Istituto Superiore Di Sanità , Rome, Italy
                [3] 3 Italian National Transplant Center—Istituto Superiore Di Sanità , Rome, Italy
                [4] 4 Azienda Zero of the Veneto Region , Padua, Italy
                [5] 5 ARIA, S.p.a. , Milan, Italy
                [6] 6 Regional Transplant Coordination , Milan, Italy
                [7] 7 Directorate General for Health , Milan, Italy
                [8] 8 General Directorate for Health , Sardinia Region, Italy
                [9] 9 Department of Clinical and Experimental Medicine , University of Pisa , Pisa, Italy
                [10] 10 CESIT Study Group is a collaborative author
                Author notes

                Edited by: Emanuel Raschi, University of Bologna, Italy

                Reviewed by: Janet Sultana, Mater Dei Hospital, Malta

                Silvia Calabria, Fondazione ReS (Ricerca e Salute)—Research and Health Foundation, Italy

                *Correspondence: Valeria Belleudi, v.belleudi@ 123456deplazio.it

                This article was submitted to Pharmacoepidemiology, a section of the journal Frontiers in Pharmacology

                Article
                959267
                10.3389/fphar.2022.959267
                9521186
                36188626
                b48a27b9-057a-4d21-8ed5-bd80c25b5614
                Copyright © 2022 Belleudi, Rosa, Finocchietti, Poggi, Marino, Massari, Spila Alegiani, Masiero, Ricci, Bedeschi, Puoti, Cardillo, Pierobon, Nordio, Ferroni, Zanforlini, Piccolo, Leone, Ledda, Carta, Garau, Lucenteforte, Davoli Addis, and CESIT Study Group.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 01 June 2022
                : 15 July 2022
                Funding
                Funded by: Agenzia Italiana Del Farmaco, Ministero Della Salute , doi 10.13039/501100003197;
                Categories
                Pharmacology
                Original Research

                Pharmacology & Pharmaceutical medicine
                immunosuppressive treatment,transplant,research network,distributed analysis,pharmacoepidemiology,pharmaco-utilization,multidisciplinary approach

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