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Nogueiras-Álvarez R, García-Saiz MDM. Tacrolimus Intrapatient Variability as a Biomarker in Solid Organ Transplantation. Clin Transplant 2025; 39:e70197. [PMID: 40504104 DOI: 10.1111/ctr.70197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2025] [Revised: 04/21/2025] [Accepted: 05/17/2025] [Indexed: 06/18/2025]
Abstract
Tacrolimus is the primary calcineurin inhibitor agent prescribed in different solid organ transplantation modalities. Among its characteristics, tacrolimus has a high inter- and intrapatient variability. Recently, tacrolimus intrapatient variability (Tac-IPV) has been proposed as a useful biomarker to predict outcomes in different types of solid organ transplantation. This work includes a systematic review of the literature that evaluates Tac-IPV influence on solid organ transplantation outcomes from inception to September 18, 2024. Although there are several publications assessing the influence of Tac-IPV in transplantation, we found that there is a lack of consensus regarding which is the best measure to evaluate Tac-IPV. Moreover, the ideal post-transplantation period for evaluating this biomarker has not been established so far. Different cut-off points have been proposed, especially in adult kidney transplantation, where most of the studies have been carried out, but these cut-off values may not be applicable to other transplantation modalities. This work includes a description of the main findings of different studies in an attempt to state what the current knowledge on the topic is in different solid organ transplantation modalities.
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Affiliation(s)
- Rita Nogueiras-Álvarez
- Clinical Pharmacology, Osakidetza Basque Health Service, Galdakao-Usansolo University Hospital, Galdakao, Bizkaia, Spain
| | - María Del Mar García-Saiz
- Clinical Pharmacology Service, Marqués de Valdecilla University Hospital, Santander, Cantabria, Spain
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Caceres Guido P, Taboada GF, Monteverde ML. Precision Dosing, Therapeutic Drug Monitoring, and Clinical Pharmacokinetics in Pediatric Kidney Transplant Patients: Principles and Practice With Emphasis on Low- and Middle-Income Countries. Pediatr Transplant 2025; 29:e70074. [PMID: 40176276 DOI: 10.1111/petr.70074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 03/13/2025] [Accepted: 03/24/2025] [Indexed: 04/04/2025]
Abstract
BACKGROUND Pediatric kidney transplantation requires complex multidisciplinary coordination. The contributions of pharmacotherapeutic aspects to this practice have been of fundamental importance, even in low- and middle-income countries (LMIC). METHODS We conducted a quasi-systematic review of the PubMed and Google Scholar databases from inception to July 2024 using Medical Subject Headings and keywords relevant to Therapeutic Drug Monitoring (TDM) and Model-Based Precision Dosing (MIPD). The quality of the articles and data collected were appraised using the appropriate critical appraisal tools and was synthesized qualitatively. RESULTS TDM and the analyses and interpretations associated with pharmacometric aspects, specifically clinical pharmacokinetics, have led to the use of modern strategies such as MIPD. These strategies allow for individually adjusted drug dosages to be optimized, making them more effective and safer for many immunosuppressants, antibiotics, antivirals, antifungals, antiepileptics, antineoplastics, and antiarrhythmics, among others. Several points of interest associated with improving the implementation and practice of TDM-MIPD, particularly challenging in LMICs, include the availability and adequate management of economic resources (such as software and laboratory supplies), the development of collaborative work with other institutions (including foreign ones), the possibility of consolidating independent management not depending on other clinical services, the need to train and maintain highly skilled professional staff for clinical and research purposes, and the establishment and maintenance of specialized educational programs. CONCLUSION Throughout the world, but especially in LMICs, there is a need to intensify strategies that allow for the more widespread application of TDM-MIPD to improve pharmacotherapeutic care for this highly vulnerable patient population.
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Affiliation(s)
- Paulo Caceres Guido
- Pharmacokinetics and Clinical Pharmacology Research Unit, Pharmacy Area, Hospital de Pediatria J.P Garrahan, Buenos Aires, Argentina
| | - Guillermo Federico Taboada
- Pharmacokinetics and Clinical Pharmacology Research Unit, Pharmacy Area, Hospital de Pediatria J.P Garrahan, Buenos Aires, Argentina
| | - Marta Lidia Monteverde
- Nephrology Department, Renal Transplant Unit, Hospital de Pediatria J.P Garrahan, Buenos Aires, Argentina
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Kreuzer M, Prüfe J, Dierks ML, Müther S, Bethe D, Büscher A, Heindl-Rusai K, Hollenbach S, Hoppe B, John-Kroegel U, Kanzelmeyer NK, Klaus G, Kranz B, Oh J, Pohl M, Rieger S, Ruckenbrodt B, Sauerstein K, Staude H, Taylan C, Thumfart J, Weitz M, Ringlstetter R, Großhennig A, Pape L. Results of a multicenter, randomized trial examining a new transition model for post-kidney transplant adolescents. Sci Rep 2025; 15:11459. [PMID: 40181098 PMCID: PMC11968839 DOI: 10.1038/s41598-025-95845-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 03/24/2025] [Indexed: 04/05/2025] Open
Abstract
Allograft loss after pediatric kidney transplantation (KTx) is highest in adolescents and young adults. Non-adherence and Health Care Transition (HCT) are important factors, but others also contribute. In the TransNephro study patients were randomized 1:1. The intervention group was included in the Berlin Transition Program (BTP) and incorporated a central case manager, a communication app, and joined transition rounds for one year before and one year after transfer. Primary endpoint was the coefficient of variation (CoV) of the trough level of the calcineurin inhibitor as a surrogate marker for medication adherence associated with graft loss. Least square (LS) mean differences and corresponding 95% confidence intervals (CIs) were estimated using an analysis of covariance (ANCOVA) model. We assessed 220 patients for eligibility. 49 patients were randomized to the intervention group and 53 to the control group. We analyzed 84 patients in the modified intention-to-treat analysis (38 intervention, 46 controls) and 60 in the per protocol analysis (25 intervention, 35 controls). We found no difference in CoV. We saw low numbers of graft-related events and observed no differences with respect to quality of life. BTP did not improve adherence and other outcome parameters. Non-adherent patients may have decided not to participate, whilst adherence of participants was already good at study start. It is therefore achallenge to design future multicenter trials on HCT that include multiple interventions.Trial registration: ISRCTN22988897, 24/04/2014, https://doi.org/10.1186/ISRCTN22988897 .
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Affiliation(s)
- Martin Kreuzer
- Clinic of Pediatrics II, Essen University Hospital, Hufelandstrasse 55, 45147, Essen, Germany
| | - Jenny Prüfe
- Clinic of Pediatrics II, Essen University Hospital, Hufelandstrasse 55, 45147, Essen, Germany
| | - Marie-Luise Dierks
- Department of Epidemiology, Social Medicine and Health System Research, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany
| | - Silvia Müther
- Berliner TransitionsProgramm (BTP), DRK-Kliniken Berlin Westend, Spandauer Damm 130, 14050, Berlin, Germany
| | - Dirk Bethe
- Division of Pediatric Nephrology, Center for Child and Adolescent Medicine, Heidelberg University Hospital, Im Neuenheimer Feld 672, 69120, Heidelberg, Germany
| | - Anja Büscher
- Clinic of Pediatrics II, Essen University Hospital, Hufelandstrasse 55, 45147, Essen, Germany
| | | | - Sabine Hollenbach
- KfH Center of Pediatric Nephrology, St. Georg Hospital, Delitzscher Str. 141, 04129, Leipzig, Germany
| | - Bernd Hoppe
- Bonn Center of Pediatric Nephrology, Im Mühlenbach 2b, 53127, Bonn, Germany
| | - Ulrike John-Kroegel
- Pediatric Nephrology, Universitätsklinikum Jena, Kastanienstraße 1, 07747, Jena, Germany
| | - Nele Kirsten Kanzelmeyer
- Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Carl- Neuberg-Strasse 1, 30625, Hannover, Germany
| | - Günter Klaus
- KfH Center of Pediatric Nephrology, University Hospital of Marburg, Baldingerstraße, 35043, Marburg, Germany
| | - Birgitta Kranz
- University Children's Hospital Münster, Albert-Schweitzer-Campus 1, 48149, Munster, Germany
| | - Jun Oh
- University Children's Hospital Eppendorf, Martinistraße 52, 20251, Hamburg, Germany
| | - Martin Pohl
- Department of General Pediatrics, Adolescent Medicine and Neonatology, Freiburg University Hospital, Heiliggeiststraße 1, 79106, Freiburg im Breisgau, Germany
| | - Susanne Rieger
- Division of Pediatric Nephrology, Center for Child and Adolescent Medicine, Heidelberg University Hospital, Im Neuenheimer Feld 672, 69120, Heidelberg, Germany
| | - Bettina Ruckenbrodt
- Children's Hospital, Olgahospital Klinikum Stuttgart, Kriegsbergstraße 60, 70174, Stuttgart, Germany
| | - Katja Sauerstein
- Children's Hospital, University of Erlangen, Maximiliansplatz 2, 91054, Erlangen, Germany
| | - Hagen Staude
- University Children's Hospital, Ernst-Heydemann-Straße 8, 18057, Rostock, Germany
| | - Christina Taylan
- Pediatric Nephrology, University Hospital of Cologne, Kerpener Str. 62, 50937, Cologne, Germany
| | - Julia Thumfart
- Department of Pediatric Nephrology, Campus Charité Virchow Klinikum, Augustenburger Platz 1, 13353, Berlin, Germany
| | - Marcus Weitz
- University Children's Hospital Tübingen, Geissweg 3, 72076, Tübingen, Germany
| | - Rieke Ringlstetter
- Institute of Biostatistics, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany
| | - Anika Großhennig
- Institute of Biostatistics, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany
| | - Lars Pape
- Clinic of Pediatrics II, Essen University Hospital, Hufelandstrasse 55, 45147, Essen, Germany.
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Gavcovich TB, Sigurjonsdottir VK, DeFreitas MJ, Serrano C, Rivas E, Jorge M, Seeherunvong W, Katsoufis C, Glaberson W, Oliva M, Mattiazzi AD, Abitbol C, Chandar J. Intrapatient tacrolimus variability is associated with medical nonadherence among pediatric kidney transplant recipients. FRONTIERS IN TRANSPLANTATION 2025; 4:1572928. [PMID: 40166382 PMCID: PMC11955662 DOI: 10.3389/frtra.2025.1572928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/07/2025] [Accepted: 03/03/2025] [Indexed: 04/02/2025]
Abstract
Background Long-term survival of kidney allografts is limited by multiple factors, including nonadherence. High intrapatient variability in tacrolimus levels (≥30%) is associated with de novo donor-specific antibody (dnDSA) formation, increased risk of rejection and graft loss. Methods We prospectively analyzed the association between tacrolimus intrapatient variability and nonadherence in pediatric kidney transplant recipients. We derived a composite adherence score from 0 to 3 points based on (1) Basel Assessment of Adherence to Immunosuppressive Medical Scale©; (2) healthcare team score; and (3) intentionally missed laboratory or clinic visits. A score of 1 or more was considered nonadherent. Tacrolimus 12 h trough levels, patient characteristics and clinical outcomes were collected. Tacrolimus IPV was calculated as the coefficient of variation. Results The nonadherent group had a significantly higher median tacrolimus intrapatient variability (31%) as compared to the adherent cohort (20%) (p < 0.001.) Tac IPV demonstrated strong predictive performance for adherence (AUC 0.772), with a particularly high sensitivity of 90% at thresholds up to 20%, offering a practical and actionable framework for assessing adherence-related risks in clinical practice. Conclusions Tacrolimus intrapatient variability may be a useful biomarker to identify nonadherence and high-risk patients, allowing for early interventions to prevent adverse graft outcomes.
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Affiliation(s)
- Tara B. Gavcovich
- Division of Pediatric Nephrology, Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, United States
- Division of Pediatric Kidney Transplantation, Department of Pediatrics, Miami Transplant Institute, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Vaka K. Sigurjonsdottir
- Division of Pediatric Nephrology, Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, United States
- Division of Pediatric Kidney Transplantation, Department of Pediatrics, Miami Transplant Institute, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Marissa J. DeFreitas
- Division of Pediatric Nephrology, Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, United States
- Division of Pediatric Kidney Transplantation, Department of Pediatrics, Miami Transplant Institute, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Claudia Serrano
- Division of Pediatric Nephrology, Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, United States
- Division of Pediatric Kidney Transplantation, Department of Pediatrics, Miami Transplant Institute, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Esther Rivas
- Division of Pediatric Nephrology, Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, United States
- Division of Pediatric Kidney Transplantation, Department of Pediatrics, Miami Transplant Institute, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Migdalia Jorge
- Division of Pediatric Nephrology, Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, United States
- Division of Pediatric Kidney Transplantation, Department of Pediatrics, Miami Transplant Institute, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Wacharee Seeherunvong
- Division of Pediatric Nephrology, Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, United States
- Division of Pediatric Kidney Transplantation, Department of Pediatrics, Miami Transplant Institute, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Chryso Katsoufis
- Division of Pediatric Nephrology, Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, United States
- Division of Pediatric Kidney Transplantation, Department of Pediatrics, Miami Transplant Institute, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Wendy Glaberson
- Division of Pediatric Nephrology, Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, United States
- Division of Pediatric Kidney Transplantation, Department of Pediatrics, Miami Transplant Institute, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Melisa Oliva
- Division of Pediatric Psychology, Department of Psychology, Jackson Health System, Miami, FL, United States
| | - Adela D. Mattiazzi
- Division of Nephrology, Department of Internal Medicine, University of Miami Miller School of Medicine and Jackson Memorial Hospital, Miami Transplant Institute, Miami, FL, United States
| | - Carolyn Abitbol
- Division of Pediatric Nephrology, Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, United States
- Division of Pediatric Kidney Transplantation, Department of Pediatrics, Miami Transplant Institute, University of Miami Miller School of Medicine, Miami, FL, United States
| | - Jayanthi Chandar
- Division of Pediatric Nephrology, Department of Pediatrics, University of Miami Miller School of Medicine, Miami, FL, United States
- Division of Pediatric Kidney Transplantation, Department of Pediatrics, Miami Transplant Institute, University of Miami Miller School of Medicine, Miami, FL, United States
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Baghai Arassi M, Feißt M, Krupka K, Awan A, Benetti E, Düzova A, Guzzo I, Kim JJ, Kranz B, Litwin M, Oh J, Büscher A, Pape L, Peruzzi L, Shenoy M, Testa S, Weber LT, Zieg J, Höcker B, Fichtner A, Tönshoff B, Cooperative European Pediatric Renal Transplant Initiative Research Network. Age-Related Differences in Rejection Rates, Infections, and Tacrolimus Exposure in Pediatric Kidney Transplant Recipients in the CERTAIN Registry. Kidney Int Rep 2024; 9:3265-3277. [PMID: 39534206 PMCID: PMC11551099 DOI: 10.1016/j.ekir.2024.08.025] [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: 06/20/2024] [Revised: 08/20/2024] [Accepted: 08/27/2024] [Indexed: 11/16/2024] Open
Abstract
Introduction Data on age-related differences in rejection rates, infectious episodes, and tacrolimus exposure in pediatric kidney transplant recipients (pKTRs) on a tacrolimus-based immunosuppressive regimen are scarce. Methods We performed a large-scale analysis of 802 pKTRs from the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) registry from 40 centers in 14 countries. The inclusion criteria were a tacrolimus-based immunosuppressive regimen and at least 2 years of follow-up. The patient population was divided into 3 age groups (infants and young children aged <6 years, school-aged children 6-12 years, and adolescents aged >12 years) to assess age-related differences in outcome. Results Median follow-up was 48 months (interquartile range [IQR], 36-72). Within the first 2 years posttransplant, infants, and young children had a significantly higher incidence of infections (80.6% vs. 55.0% in adolescents, P < 0.001) and a significantly higher number of cumulative hospital days (median 13 days vs. 7 days in adolescents, P < 0.001). Adolescents had a significantly higher rate of biopsy-proven acute rejection episodes in the first-year posttransplant (21.7%) than infants and young children (12.6%, P = 0.007). Infants and young children had significantly lower tacrolimus trough levels, lower tacrolimus concentration-to-dose (C/D) ratios as an approximation for higher tacrolimus clearance, and higher tacrolimus interpatient variability (TacIPV) (all P < 0.01) than adolescents. Conclusion This is the largest study to date in European pKTRs on a tacrolimus-based immunosuppressive regimen, and it shows important age-related differences in rejection rates, infection episodes, as well as tacrolimus exposure and clearance. This data suggests that immunosuppressive therapy in pKTRs should be tailored and personalized according to the age-specific risk profiles of this heterogeneous patient population. The data may serve as a benchmark for future studies with novel immunosuppressive drugs.
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Affiliation(s)
- Maral Baghai Arassi
- Department of Pediatrics I, Medical Faculty, Heidelberg University, University Children’s Hospital Heidelberg, Heidelberg, Germany
- Structural and Computational Biology Unit, European Molecular Biology Laboratory Heidelberg, Heidelberg, Germany
| | - Manuel Feißt
- Institute of Medical Biometry, Heidelberg University, Heidelberg, Germany
| | - Kai Krupka
- Department of Pediatrics I, Medical Faculty, Heidelberg University, University Children’s Hospital Heidelberg, Heidelberg, Germany
| | - Atif Awan
- National Pediatric Haemodialysis Centre and Renal Transplant Unit, Temple Street Children’s University Hospital, Dublin, Ireland
| | - Elisa Benetti
- Pediatric Nephrology Unit, Department of Women’s and Children’s Health, Padua University Hospital, Italy
| | - Ali Düzova
- Division of Pediatric Nephrology, Hacettepe University Faculty of Medicine, Ankara, Türkiye
| | - Isabella Guzzo
- Division of Nephrology, Dialysis and Transplant Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Jon Jin Kim
- Department of Pediatric Nephrology, Nottingham University Hospitals, Nottingham, UK
| | - Birgitta Kranz
- Department of General Pediatrics, University Children’s Hospital Münster, Münster, Germany
| | - Mieczysław Litwin
- Department of Nephrology, Kidney Transplantation and Hypertension, The Children's Memorial Health Institute, Warsaw, Poland
| | - Jun Oh
- Division of Pediatric Nephrology, University Hamburg-Eppendorf, Hamburg, Germany
| | - Anja Büscher
- Department of Pediatrics II, University Hospital of Essen, Essen, Germany
| | - Lars Pape
- Department of Pediatrics II, University Hospital of Essen, Essen, Germany
| | - Licia Peruzzi
- Pediatric Nephrology Unit, Regina Margherita Department, Azienda Ospedaliero-Universitaria Città Della Salute e della Scienza, Torino, Italy
| | - Mohan Shenoy
- Department of Pediatric Nephrology, Royal Manchester Children's Hospital, Manchester, UK
| | - Sara Testa
- Pediatric Nephrology Unit, Dialysis and Transplantation Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Lutz T. Weber
- Pediatric Nephrology, Children's and Adolescents' Hospital, University Hospital of Cologne, Faculty of Medicine, University of Cologne, Köln, Germany
| | - Jakub Zieg
- Department of Pediatrics, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic
| | - Britta Höcker
- Department of Pediatrics I, Medical Faculty, Heidelberg University, University Children’s Hospital Heidelberg, Heidelberg, Germany
| | - Alexander Fichtner
- Department of Pediatrics I, Medical Faculty, Heidelberg University, University Children’s Hospital Heidelberg, Heidelberg, Germany
| | - Burkhard Tönshoff
- Department of Pediatrics I, Medical Faculty, Heidelberg University, University Children’s Hospital Heidelberg, Heidelberg, Germany
| | - Cooperative European Pediatric Renal Transplant Initiative Research Network
- Department of Pediatrics I, Medical Faculty, Heidelberg University, University Children’s Hospital Heidelberg, Heidelberg, Germany
- Structural and Computational Biology Unit, European Molecular Biology Laboratory Heidelberg, Heidelberg, Germany
- Institute of Medical Biometry, Heidelberg University, Heidelberg, Germany
- National Pediatric Haemodialysis Centre and Renal Transplant Unit, Temple Street Children’s University Hospital, Dublin, Ireland
- Pediatric Nephrology Unit, Department of Women’s and Children’s Health, Padua University Hospital, Italy
- Division of Pediatric Nephrology, Hacettepe University Faculty of Medicine, Ankara, Türkiye
- Division of Nephrology, Dialysis and Transplant Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
- Department of Pediatric Nephrology, Nottingham University Hospitals, Nottingham, UK
- Department of General Pediatrics, University Children’s Hospital Münster, Münster, Germany
- Department of Nephrology, Kidney Transplantation and Hypertension, The Children's Memorial Health Institute, Warsaw, Poland
- Division of Pediatric Nephrology, University Hamburg-Eppendorf, Hamburg, Germany
- Department of Pediatrics II, University Hospital of Essen, Essen, Germany
- Pediatric Nephrology Unit, Regina Margherita Department, Azienda Ospedaliero-Universitaria Città Della Salute e della Scienza, Torino, Italy
- Department of Pediatric Nephrology, Royal Manchester Children's Hospital, Manchester, UK
- Pediatric Nephrology Unit, Dialysis and Transplantation Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
- Pediatric Nephrology, Children's and Adolescents' Hospital, University Hospital of Cologne, Faculty of Medicine, University of Cologne, Köln, Germany
- Department of Pediatrics, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic
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Ettenger RB, Seifert ME, Blydt-Hansen T, Briscoe DM, Holman J, Weng PL, Srivastava R, Fleming J, Malekzadeh M, Pearl M. Detection of Subclinical Rejection in Pediatric Kidney Transplantation: Current and Future Practices. Pediatr Transplant 2024; 28:e14836. [PMID: 39147695 DOI: 10.1111/petr.14836] [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: 04/18/2024] [Revised: 07/19/2024] [Accepted: 07/22/2024] [Indexed: 08/17/2024]
Abstract
INTRODUCTION The successes in the field of pediatric kidney transplantation over the past 60 years have been extraordinary. Year over year, there have been significant improvements in short-term graft survival. However, improvements in longer-term outcomes have been much less apparent. One important contributor has been the phenomenon of low-level rejection in the absence of clinical manifestations-so-called subclinical rejection (SCR). METHODS Traditionally, rejection has been diagnosed by changes in clinical parameters, including but not limited to serum creatinine and proteinuria. This review examines the shortcomings of this approach, the effects of SCR on kidney allograft outcome, the benefits and drawbacks of surveillance biopsies to identify SCR, and new urine and blood biomarkers that define the presence or absence of SCR. RESULTS Serum creatinine is an unreliable index of SCR. Surveillance biopsies are the method most utilized to detect SCR. However, these have significant drawbacks. New biomarkers show promise. These biomarkers include blood gene expression profiles and donor derived-cell free DNA; urine gene expression profiles; urinary cytokines, chemokines, and metabolomics; and other promising blood and urine tests. CONCLUSION Specific emphasis is placed on studies carried out in pediatric kidney transplant recipients. TRIAL REGISTRATION ClinicalTrials.gov: NCT03719339.
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Affiliation(s)
- Robert B Ettenger
- Division of Nephrology, Department of Pediatrics, UCLA Mattel Children's Hospital, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Michael E Seifert
- Division of Pediatric Nephrology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Tom Blydt-Hansen
- Multi-Organ Transplant Program, British Columbia Children's Hospital, University of British Columbia, Vancouver, British Columbia, Canada
| | - David M Briscoe
- Division of Nephrology, Department of Pediatrics Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - John Holman
- Transplant Genomics Inc., Framingham, Massachusetts, USA
| | - Patricia L Weng
- Division of Nephrology, Department of Pediatrics, UCLA Mattel Children's Hospital, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Rachana Srivastava
- Division of Nephrology, Department of Pediatrics, UCLA Mattel Children's Hospital, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - James Fleming
- Transplant Genomics Inc., Framingham, Massachusetts, USA
| | - Mohammed Malekzadeh
- Division of Nephrology, Department of Pediatrics, UCLA Mattel Children's Hospital, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
| | - Meghan Pearl
- Division of Nephrology, Department of Pediatrics, UCLA Mattel Children's Hospital, David Geffen School of Medicine at UCLA, Los Angeles, California, USA
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7
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Xie W, Fan S, Liu R, Yan W, Su C, Zheng K, Wang X, Wang Z. Tacrolimus intra-patient variability measures and its associations with allograft clinical outcomes in kidney transplantation. Transplant Rev (Orlando) 2024; 38:100842. [PMID: 38537484 DOI: 10.1016/j.trre.2024.100842] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 03/14/2024] [Accepted: 03/15/2024] [Indexed: 06/16/2024]
Abstract
AIMS Tacrolimus (Tac) is commonly prescribed in solid organ transplantation to prevent immune-mediated damage to the graft. However, its pharmacokinetics show substantial variability between and within patients. Intra-patient variability of tacrolimus (Tac-IPV) has emerged as a novel marker to predict transplant outcomes. Numerous studies report varying associations between Tac-IPV and clinical outcomes, with Tac-IPV measures showing wide discrepancies among these studies. This inconsistency could be a significant factor that influences the various outcomes reported in different studies. Our review comprehensively assesses the relationship between various Tac-IPV measures and their associations with clinical outcomes in transplant patients. METHODS A comprehensive literature search was conducted using the PubMed and Embase databases, covering the period from 2004 to March 31, 2023. The search focused on studies that examined the relationship between Tac-IPV and clinical outcomes in kidney transplantation (KT). The inclusion criteria were specific to studies addressing Tac-IPV, including measures such as standard deviation (SD), coefficient of variation (CV), time-weighted coefficient of variability (CV), mean absolute deviation (MAD), and Tac variability score (TVS). Clinical outcomes included the development of de novo donor-specific antibodies (dnDSA), rejection episodes, graft loss, and graft failure. RESULTS Among the 33 studies that met the inclusion criteria, a notable proportion presented conflicting findings in their assessment of various Tac-IPV measures regarding dnDSA, rejection episodes, graft loss, and graft failure. CONCLUSIONS Most studies have identified a correlation between high Tac-IPV and poor clinical outcomes; however, this relationship is multifactorial. Influencing factors include the metabolic status of KT patients, the timing of Tac-IPV calculations, and the criteria for defining high and low Tac-IPV thresholds, including the size and selection method. CV, MAD, and TWCV are the metrics that are most frequently used to determine Tac-IPV. Additionally, most of the methods for establishing Tac-IPV thresholds typically employ receiver operating characteristic (ROC) curves and median values. It is also notable that studies examining the clinical significance of Tac-IPV often include tacrolimus levels measured six months after kidney transplantation.
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Affiliation(s)
- Wenmin Xie
- Department of Pharmacy, Shanghai Changhai Hospital, Naval Medical University, Shanghai, People's Republic of China; College of life sciences and Biopharmaceuticals, Shenyang Pharmaceutical University, Shenyang, People's Republic of China
| | - Shupan Fan
- Department of Pharmacy, Shanghai Changhai Hospital, Naval Medical University, Shanghai, People's Republic of China; Department of Gastroenterology, Digestive Endoscopy Center, Changhai Hospital, Naval Medical University, Shanghai, People's Republic of China
| | - Ruolin Liu
- Department of Pharmacy, Shanghai Changhai Hospital, Naval Medical University, Shanghai, People's Republic of China; College of life sciences and Biopharmaceuticals, Shenyang Pharmaceutical University, Shenyang, People's Republic of China
| | - Wencheng Yan
- Department of Pharmacy, Shanghai Changhai Hospital, Naval Medical University, Shanghai, People's Republic of China; School of Pharmacy, Bengbu Medical University, Bengbu, People's Republic of China
| | - Chengxin Su
- Department of Pharmacy, Shanghai Changhai Hospital, Naval Medical University, Shanghai, People's Republic of China; College of life sciences and Biopharmaceuticals, Shenyang Pharmaceutical University, Shenyang, People's Republic of China
| | - Kaile Zheng
- Department of Pharmacy, Shanghai Changhai Hospital, Naval Medical University, Shanghai, People's Republic of China; School of Pharmacy, Bengbu Medical University, Bengbu, People's Republic of China
| | - Xuebin Wang
- Department of pharmacy, Shanghai Children's Hospital, School of medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China.
| | - Zhuo Wang
- Department of Pharmacy, Shanghai Changhai Hospital, Naval Medical University, Shanghai, People's Republic of China; College of life sciences and Biopharmaceuticals, Shenyang Pharmaceutical University, Shenyang, People's Republic of China; Department of Gastroenterology, Digestive Endoscopy Center, Changhai Hospital, Naval Medical University, Shanghai, People's Republic of China; School of Pharmacy, Bengbu Medical University, Bengbu, People's Republic of China.
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8
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Chen F, Yong JK, Shen C, Zhou T, Feng M, Wan P, Luo Y, Lin H, Qian Y, Xia Q. High intra-patient variability of tacrolimus within post-operative 1 month predicted worse 1-year outcomes in pediatric liver transplant recipients. Eur J Clin Pharmacol 2024:10.1007/s00228-024-03663-z. [PMID: 38502358 DOI: 10.1007/s00228-024-03663-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Accepted: 03/04/2024] [Indexed: 03/21/2024]
Abstract
BACKGROUND The pharmacokinetics of tacrolimus (TAC) show high intra-patient variability (IPV), which is associated with poor long-term outcomes following adult liver transplantation (LT). However, this relationship remains to be confirmed in pediatric liver transplant (PLT) recipients. The present study aimed to investigate the association between TAC IPV and grafts or patient outcomes after pediatric liver transplantion. METHODS This retrospective study included 848 PLT recipients (including infants) between January, 2016, and June, 2021. The IPV of TAC concentrations was estimated by calculating the coefficient of variation (CV) of trough concentrations in whole blood within 1 month after transplantation. Patients were categorized into two groups, low IPV (CV < 45%) and high IPV (CV ≥ 45%), based on the third quartile of the CV distribution. RESULTS A total of 848 patients were included in our study. The low CV group included 614 patients, with a mean TAC trough concentration of 8.59 ± 1.65 ng/ml and a median CV of 32.37%. In contrast, the high CV group included 214 patients, the mean TAC trough concentration and median CV were 8.81 ± 2.00 ng/ml and 54.88%, respectively. The median hospital duration was significantly higher in the high CV group (22 days vs. 20 days, P = 0.01). Univariate analysis was performed to evaluate the significant differences in 1-year recipient survival (P = 0.041) and 1-year graft survival (P = 0.005) between the high- and low-CV groups. Moreover, high CV (HR 2.316, 95%CI 1.026-5.231, P = 0.043) and persistent EBV viremia (HR 13.165, 95%CI 3.090-56.081, P < 0.001) were identified as independent risk factors for 1- year mortality after PLT. CONCLUSIONS PLT recipients with high TAC trough concentration of CV in the first month were associated with poor 1-year outcomes. This CV calculation provides a valuable strategy to monitor TAC exposure.
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Affiliation(s)
- Fang Chen
- Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, People's Republic of China
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, No. 1630 Dongfang Road, Shanghai, 200127, People's Republic of China
| | - June-Kong Yong
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, No. 1630 Dongfang Road, Shanghai, 200127, People's Republic of China
| | - Chuan Shen
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, No. 1630 Dongfang Road, Shanghai, 200127, People's Republic of China
| | - Tao Zhou
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, No. 1630 Dongfang Road, Shanghai, 200127, People's Republic of China
| | - Mingxuan Feng
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, No. 1630 Dongfang Road, Shanghai, 200127, People's Republic of China
| | - Ping Wan
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, No. 1630 Dongfang Road, Shanghai, 200127, People's Republic of China
| | - Yi Luo
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, No. 1630 Dongfang Road, Shanghai, 200127, People's Republic of China
| | - Houwen Lin
- Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, People's Republic of China
| | - Yongbing Qian
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, No. 1630 Dongfang Road, Shanghai, 200127, People's Republic of China.
| | - Qiang Xia
- Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, No. 1630 Dongfang Road, Shanghai, 200127, People's Republic of China.
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9
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Dobbels F, Wray J. Medication adherence in pediatric kidney transplantation: How to build a bridge over troubled water. Pediatr Transplant 2024; 28:e14663. [PMID: 38012099 DOI: 10.1111/petr.14663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 10/13/2023] [Accepted: 11/16/2023] [Indexed: 11/29/2023]
Abstract
Adhering to the immunosuppressive regimen remains one of the biggest challenges for children and adolescents after kidney transplantation. The first paper on nonadherence, co-authored by Dr. Fine, appeared in Pubmed over 45 years ago. Since then, many clinicians and researchers tried to better understand nonadherence and are looking for effective ways to support young people in implementing the complex medication regimen in their daily lives. As a tribute to Dr. Fine, we conducted a comprehensive review providing an overview of adherence-enhancing interventions in the field of pediatric kidney transplantation, thereby focusing on strategies that not only are effective but can also be embedded in daily clinical practice successfully and sustainably. This overview is preceded by a discussion about how to find out who is in need of supportive interventions. We will also argue that interventions should already start before pediatric kidney transplantation and discuss how to decide whether or not a young patient with nonadherence-induced graft loss should undergo retransplantation. We hope this comprehensive overview will rekindle the hope that we can finally turn the tide and beat one of pediatric kidney transplantation's main enemies.
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Affiliation(s)
- Fabienne Dobbels
- Department of Public Health and Primary Care, KU Leuven, Leuven, Belgium
| | - Jo Wray
- Centre for Outcomes and Experience Research in Children's Health, Illness and Disability (ORCHID), London, UK
- Heart and Lung Directorate, Great Ormond Street Hospital for Children, London, UK
- Institute of Cardiovascular Science, University College London, London, UK
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10
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Sharma A, Verma S, Mirzai S, Viswanathan V, Kapoor S, Hariharan S, Dew MA, Puttarajappa CM. Implementing a self-reported immunosuppression adherence questionnaire to screen for non-adherence in routine care of kidney transplant recipients. Clin Transplant 2024; 38:e15157. [PMID: 37792310 DOI: 10.1111/ctr.15157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 09/20/2023] [Accepted: 09/24/2023] [Indexed: 10/05/2023]
Abstract
INTRODUCTION Self-reported measures of immunosuppression adherence have been largely examined in research settings. METHODS In this single center study of 610 kidney transplant recipients, we examined if a voluntary, non-anonymous self-report measure could identify non-adherence in a routine clinic setting and how patients perceived such a measure. Non-adherence was measured using the Basel Assessment of Adherence to Immunosuppressive Medications Scale (BAASIS) and patient perception was elicited using a customized questionnaire. RESULTS Non-responders to the survey (15%) were younger, more likely to be black, and less likely to have had a pre-emptive transplant. Among complete responders (n = 485), 38% reported non-adherence with non-adherent patients being younger (54 y vs. 60 y; p = .01), less likely to have been on dialysis pre-transplant (59% vs. 68%; p = .04), further out from transplant (37 vs. 22 months; p < .001) and had more rejections in the preceding year (8% vs. 3%; p = .02). Self-reported non-adherence was associated with higher calcineurin inhibitor intra-patient variability (27.4% vs. 24.5%; p = .02), but not with donor-specific antibody detection (27.8% vs. 21.2%, p = .15). Of patients providing feedback (n = 500), the majority of patients felt comfortable reporting adherence (92%), that the survey was relevant to their visit (71%), and that the survey did not interfere with their clinic visit (88%). CONCLUSION In summary, a self-reported questionnaire during clinic visits identified immunosuppression non-adherence in a significant proportion of patients and was well received by patients. Integrating self-report measures into routine post-transplant care may enable early identification of non-adherence.
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Affiliation(s)
- Akhil Sharma
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Siddharth Verma
- Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Saeid Mirzai
- Department of Medicine, Cleveland Clinic, Cleveland, Ohio, USA
| | - Vignesh Viswanathan
- Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Sanjana Kapoor
- Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Sundaram Hariharan
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Mary Amanda Dew
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Chethan M Puttarajappa
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Department of Medicine, Renal-Electrolyte Division, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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11
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Chen F, Yang X, Li H, Zeng X, Deng Z, Wang H, Jin Y, Qiu C, Shi Z. Improved LC-MS/MS method for the simultaneous quantification of tacrolimus and cyclosporine A in human blood and application to therapeutic drug monitoring. Biomed Chromatogr 2023; 37:e5751. [PMID: 37772369 DOI: 10.1002/bmc.5751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2023] [Revised: 08/28/2023] [Accepted: 09/07/2023] [Indexed: 09/30/2023]
Abstract
In order to facilitate therapeutic drug monitoring of tacrolimus and cyclosporine A in clinical practice, a simple, rapid, robust, sensitive and specific LC-MS/MS assay was developed and validated for the simultaneous determination of tacrolimus and cyclosporine A in human whole blood. Erythrocytes were destroyed using internal standard solution with 10% (w/v) zinc sulfate in water. The analytes were extracted from 100 μl of whole blood by protein precipitation with acetonitrile. Chromatographic separation was conducted on a Kinetex PFP column (60°C) by a gradient elution with a flow rate of 0.450 ml/min in 2.5 min. Quantitative analysis was performed using electrospray ionization and multiple reaction monitoring in positive ionization mode. The method was fully validated as per current guidelines on bioanalytical methodologies of the US Food and Drug Administration and European Medicines Agency. The method developed was applied successfully in analyzing clinical samples from patients administered tacrolimus or cyclosporine A. The sample treatment procedure was rationalized and improved to fulfill the complete target extraction. The chromatography conditions were optimized to achieve rapid and accurate quantification of both analytes. This method may be beneficial as a constructive input for the therapeutic drug monitoring of tacrolimus and cyclosporine A in obtaining individualized therapy.
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Affiliation(s)
- Feng Chen
- Department of Clinical Pharmacy, Hunan University of Medicine General Hospital, Huaihua, China
| | - Xiaoxia Yang
- Department of Endocrine Metabolism and Clinical Nutrition, Hunan University of Medicine General Hospital, Huaihua, China
| | - Huanhuan Li
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, China
- School of Pharmacy, Queen's University Belfast, Belfast, UK
| | - Xiaodan Zeng
- Department of Clinical Pharmacy, Hunan University of Medicine General Hospital, Huaihua, China
- Department of Evidence-Based Medicine and Clinical Center, Hunan University of Medicine General Hospital, Huaihua, China
| | - Ziwei Deng
- Department of Clinical Pharmacy, Hunan University of Medicine General Hospital, Huaihua, China
- Department of Evidence-Based Medicine and Clinical Center, Hunan University of Medicine General Hospital, Huaihua, China
| | - Hongqiang Wang
- Department of Clinical Pharmacy, Hunan University of Medicine General Hospital, Huaihua, China
- Department of Evidence-Based Medicine and Clinical Center, Hunan University of Medicine General Hospital, Huaihua, China
| | - Yuanxiang Jin
- Department of Clinical Pharmacy, Hunan University of Medicine General Hospital, Huaihua, China
- Department of Evidence-Based Medicine and Clinical Center, Hunan University of Medicine General Hospital, Huaihua, China
| | - Chengfeng Qiu
- Department of Clinical Pharmacy, Hunan University of Medicine General Hospital, Huaihua, China
- Department of Evidence-Based Medicine and Clinical Center, Hunan University of Medicine General Hospital, Huaihua, China
| | - Zhihua Shi
- Department of Clinical Pharmacy, Hunan University of Medicine General Hospital, Huaihua, China
- Department of Evidence-Based Medicine and Clinical Center, Hunan University of Medicine General Hospital, Huaihua, China
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12
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Chambord J, Chauveau B, Djabarouti S, Vignaud J, Taton B, Moreau K, Visentin J, Merville P, Xuereb F, Couzi L. Measurement of the Immunosuppressant Possession Ratio by Transplant Clinical Pharmacists Captures a Non-Adherence Associated With Antibody-Mediated Rejection. Transpl Int 2023; 36:11962. [PMID: 38089004 PMCID: PMC10713790 DOI: 10.3389/ti.2023.11962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Accepted: 11/16/2023] [Indexed: 12/18/2023]
Abstract
Our objective was to calculate an immunosuppressant possession ratio (IPR) to diagnose non-adherence at the time of antibody-mediated rejection (ABMR). IPR was defined as the ratio of number of pills collected at the pharmacy to the number of pills prescribed over a defined period. In a first cohort of 91 kidney transplant recipients (KTRs), those with an IPR < 90% had more frequently a tacrolimus through level coefficient of variation >30% than patients with an IPR = 100% (66.7% vs. 29.4%, p = 0.05). In a case-control study, 26 KTRs with ABMR had lower 6 months IPRs than 26 controls (76% vs. 99%, p < 0.001). In KTRs with ABMR, non-adherence was more often diagnosed by a 6 months IPR < 90% than by clinical suspicion (73.1% vs 30.8%, p = 0.02). In the multivariable analysis, only de novo DSA and 6 months IPR < 90% were independently associated with ABMR, whereas clinical suspicion was not (odds ratio, 4.73; 95% CI, 1.17-21.88; p = 0.03; and odds ratio, 6.34; 95% CI, 1.73-25.59; p = 0.007, respectively). In summary, IPR < 90% is a quantifiable tool to measure immunosuppressant non-adherence. It is better associated with ABMR than clinical suspicion of non-adherence.
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Affiliation(s)
- Jérémy Chambord
- Service de Pharmacie, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
| | - Bertrand Chauveau
- Service d’Anatomopathologie, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
- CNRS-UMR 5164 ImmunoConcEpT, Université de Bordeaux, Bordeaux, France
| | - Sarah Djabarouti
- Service de Pharmacie, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
- INSERM U1312 BRIEC, Université de Bordeaux, Bordeaux, France
| | - Jean Vignaud
- Service de Pharmacie, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
| | - Benjamin Taton
- Service de Néphrologie, Transplantation, Dialyse, Aphérèse, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
| | - Karine Moreau
- Service de Néphrologie, Transplantation, Dialyse, Aphérèse, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
| | - Jonathan Visentin
- CNRS-UMR 5164 ImmunoConcEpT, Université de Bordeaux, Bordeaux, France
- Service d’Immunologie et Immunogénétique, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
| | - Pierre Merville
- CNRS-UMR 5164 ImmunoConcEpT, Université de Bordeaux, Bordeaux, France
- Service de Néphrologie, Transplantation, Dialyse, Aphérèse, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
| | - Fabien Xuereb
- Service de Pharmacie, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
- INSERM U1034, Université de Bordeaux, Bordeaux, France
| | - Lionel Couzi
- CNRS-UMR 5164 ImmunoConcEpT, Université de Bordeaux, Bordeaux, France
- Service de Néphrologie, Transplantation, Dialyse, Aphérèse, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France
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13
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An S, Lee S, Rhu J, Kim JM, Choi GS, Joh JW. Safety and Efficacy of Conversion to Once-Daily Tacrolimus from Twice-Daily Tacrolimus in Pediatric Liver Transplant Recipients. J Pediatr Surg 2023; 58:2054-2058. [PMID: 37277238 DOI: 10.1016/j.jpedsurg.2023.05.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 04/21/2023] [Accepted: 05/07/2023] [Indexed: 06/07/2023]
Abstract
BACKGROUND Nonadherence to immunosuppression is the most common cause of late acute rejection in pediatric liver transplant (LT) recipients. A prolonged-release once-daily tacrolimus formulation was developed to improve adherence and long-term allograft survival. METHODS We screened 179 pediatric LT recipients who converted from twice-daily tacrolimus (TD-TAC) to once-daily tacrolimus (OD-TAC) between February 2011 and September 2019. RESULTS One hundred seventy-nine recipients converted to OD-TAC and were followed for 18 months. 152 OD-TAC-converted recipients (84.9%) experienced uneventful follow-up, while 21 recipients showed LFT elevation. Four recipients had biopsy-proven acute rejection within six months of conversion, all of which were successfully treated with steroid pulse. 166 recipients (92.7%) remain on OD-TAC and 13 (7.3%) were switched back to TD-TAC. The mean tacrolimus trough level significantly decreased three months following conversion (3.14 ± 1.9 ng/mL) compared with pre-conversion levels (3.69 ± 1.98 ng/mL). Mean tacrolimus trough levels remained unchanged from 3 months to 12 months following conversion. Percent coefficient of variation of tacrolimus trough levels decreased significantly from 32.5 ± 16.4 ng/mL to 27.5 ± 15.6 ng/mL after conversion to OD-TAC, reflecting a decrease in variation of tacrolimus trough levels following conversion. CONCLUSIONS Conversion to OD-TAC in pediatric LT recipients with stable graft function is safe and effective. LEVEL OF EVIDENCE Level IV.
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Affiliation(s)
- SungHyo An
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Sanghoon Lee
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
| | - Jinsoo Rhu
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Jong Man Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Gyu-Seong Choi
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Jae-Won Joh
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
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14
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Vengadessane S, Viglietti D, Sauvageon H, Glotz D, Lefaucheur C, Madelaine I, Deville L. [Medication adherence in renal transplantation: Evaluation, predictive factors and impact on humoral alloreactivity]. ANNALES PHARMACEUTIQUES FRANÇAISES 2023; 81:152-162. [PMID: 35792151 DOI: 10.1016/j.pharma.2022.06.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 05/30/2022] [Accepted: 06/29/2022] [Indexed: 01/07/2023]
Abstract
OBJECTIVES The aims of this study were to assess medication adherence to immunosuppressive treatment in kidney transplanted patients, to identify predictive factors of medication non-adherence and to analyse its impact on the development of Donor Specific Antibodies (DSA) de novo, biomarkers of rejection in transplant recipients. METHODS A cross-sectional single-centre study was conducted to assess medication adherence to immunosuppressive treatment with the BAASIS (Basel Assessment of Adherence Scale for Immunosuppressives) self-report questionnaire. Univariate and multivariate analyses were performed to determine non-adherence predictive factors and its role in the development of DSA de novo. RESULTS A total of 212 renal transplanted patients completed the BAASIS questionnaire: 36,3 % were non-adherent to their immunosuppressive treatment. Patient's age and taking azathioprine were independent predictors of non-adherence and "married or living together" family status was a protective factor in the multivariate analysis. Medication non-adherence was associated with DSA de novo development in the multivariate model and it multiplied their risk of development by 3. CONCLUSIONS This study, which detected a large proportion of patients who did not adhere to immunosuppressive treatment, highlighted non-adherence predictors and showed the association between non-adherence and development of DSA de novo. In case of non-adherent behavior, it is crucial to set up a personalised support for patients with a multidisciplinary approach of therapeutic education, in which the clinical pharmacist has a role.
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Affiliation(s)
- Subashini Vengadessane
- Service de pharmacie, hôpital Saint-Louis (APHP), 1, avenue Claude-Vellefaux, 75010 Paris, France.
| | - Denis Viglietti
- Service de néphrologie, hôpital Saint-Louis (APHP), 1, avenue Claude-Vellefaux, 75010 Paris, France
| | - Hélène Sauvageon
- Service de pharmacie, hôpital Saint-Louis (APHP), 1, avenue Claude-Vellefaux, 75010 Paris, France
| | - Denis Glotz
- Service de néphrologie, hôpital Saint-Louis (APHP), 1, avenue Claude-Vellefaux, 75010 Paris, France
| | - Carmen Lefaucheur
- Service de néphrologie, hôpital Saint-Louis (APHP), 1, avenue Claude-Vellefaux, 75010 Paris, France
| | - Isabelle Madelaine
- Service de pharmacie, hôpital Saint-Louis (APHP), 1, avenue Claude-Vellefaux, 75010 Paris, France
| | - Laure Deville
- Service de pharmacie, hôpital Saint-Louis (APHP), 1, avenue Claude-Vellefaux, 75010 Paris, France
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15
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Comparison of Tacrolimus Intra-Patient Variability during 6-12 Months after Kidney Transplantation between CYP3A5 Expressers and Nonexpressers. J Clin Med 2022; 11:jcm11216320. [PMID: 36362548 PMCID: PMC9658797 DOI: 10.3390/jcm11216320] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 10/19/2022] [Accepted: 10/24/2022] [Indexed: 12/05/2022] Open
Abstract
A high intra-patient variability (IPV) of tacrolimus exposure is associated with poor long-term kidney transplantation outcomes. To assess the influence of cytochrome P450 (CYP) 3A5 genetic polymorphisms on tacrolimus IPV, 188 clinically stable kidney transplant recipients, who had received an immediate-release tacrolimus-based immunosuppressive regimen, were enrolled in this retrospective cohort study. Genotyping of CYP3A5*3 (rs776746) was performed and 110 (58.5%) were identified as CYP3A5 expressers and 78 (41.5%) as nonexpressers. Whole blood tacrolimus concentrations were analyzed by chemiluminescent microparticle immunoassay. Dose-adjusted trough tacrolimus concentrations (C0/D) measured at months 6, 9, and 12 were used to determine IPV. There were no significant differences in the IPV estimated by the coefficient of variation, the IPV calculated by mean absolute deviation method, and the proportions of recipients with the IPV estimated by the coefficient of variation of 30% or more between CYP3A5 expressers and nonexpressers (p = 0.613, 0.686, and 0.954, respectively). Tacrolimus C0/D in CYP3A5 expressers was approximately half of those in nonexpressers, overall (p < 0.001). In both CYP3A5 expressers and nonexpressers, tacrolimus C0/D increased gradually from month 6 to month 12 (p = 0.021). There was no evidence that the CYP3A5 polymorphisms significantly influence tacrolimus IPV during the 6 to 12 months after kidney transplantation.
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16
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Choi JS, Ko H, Kim HK, Chung C, Han A, Min SK, Ha J, Kang HG, Ha IS, Min S. Effects of tacrolimus intrapatient variability and CYP3A5 polymorphism on the outcomes of pediatric kidney transplantation. Pediatr Transplant 2022; 26:e14297. [PMID: 35466485 DOI: 10.1111/petr.14297] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 03/16/2022] [Accepted: 04/07/2022] [Indexed: 12/17/2022]
Abstract
BACKGROUND The intrapatient variability (IPV) of tacrolimus (Tac) is associated with the long-term outcome of kidney transplantation. The CYP3A single-nucleotide polymorphism (SNP) may affect the IPV of Tac. We investigated the impact of IPV and genetic polymorphism in pediatric patients who received kidney transplantation. METHODS A total of 202 pediatric renal transplant recipients from 2000 to 2016 were analyzed retrospectively. The IPV was calculated between 6 and 12 months after surgery. Among these patients, CYP3A5 polymorphism was analyzed in 67 patients. RESULTS The group with high IPV had a significantly higher rate of de novo donor-specific human leukocyte antigen antibodies (dnDSA) development (35.7% vs. 16.7%, p = .003). The high IPV group also had a higher incidence of T-cell-mediated rejection (TCMR; p < .001). The high IPV had no significant influence on Epstein-Barr virus, cytomegalovirus, and BK virus viremia but was associated with the incidence of posttransplant lymphoproliferative disorders (p = .003). Overall, the graft survival rate was inferior in the high IPV group (p < .001). The CYP3A5 SNPs did not significantly affect the IPV of Tac. In the CYP3A5 expressor group, however, the IPV was significantly associated with the TCMR-free survival rate (p < .001). CONCLUSION The IPV of Tac had a significant impact on dnDSA development, occurrence of acute TCMR, and graft failure in pediatric patients who received renal transplantation. CYP3A5 expressors with high IPV of Tac showed worse outcomes, while the CYP3A5 polymorphism had no impact on IPV of Tac.
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Affiliation(s)
- Jin Sun Choi
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Hyunmin Ko
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Hyo Kee Kim
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Chris Chung
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Ahram Han
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Seung-Kee Min
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Jongwon Ha
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea.,Transplantation Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Hee Gyung Kang
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Il Soo Ha
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Sangil Min
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
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17
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Piburn KH, Sigurjonsdottir VK, Indridason OS, Maestretti L, Patton MV, McGrath A, Palsson R, Gallo A, Chaudhuri A, Grimm PC. Patterns in Tacrolimus Variability and Association with De Novo Donor-Specific Antibody Formation in Pediatric Kidney Transplant Recipients. Clin J Am Soc Nephrol 2022; 17:1194-1203. [PMID: 35882506 PMCID: PMC9435976 DOI: 10.2215/cjn.16421221] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Accepted: 05/11/2022] [Indexed: 01/27/2023]
Abstract
BACKGROUND AND OBJECTIVES High tacrolimus intrapatient variability has been associated with inferior graft outcomes in patients with kidney transplants. We studied baseline patterns of tacrolimus intrapatient variability in pediatric patients with kidney transplants and examined these patterns in relation to C1q-binding de novo donor-specific antibodies. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS All tacrolimus levels in participants who underwent kidney-only transplantation at a single pediatric center from 2004 to 2018 (with at least 12-month follow-up, followed until 2019) were analyzed to determine baseline variability. Intrapatient variability was defined using the coefficient of variation (SD/mean ×100%) of all samples in a 6-month moving window. Routine de novo donor-specific antibody measurements were available for a subgroup of patients transplanted in 2010-2018. Cox proportional hazards models using tacrolimus intrapatient variability as a time-varying variable were used to examine the association between intrapatient variability and graft outcomes. The primary outcome of interest was C1q-binding de novo donor-specific antibody formation. RESULTS Tacrolimus intrapatient variability developed a steady-state baseline of 30% at 10 months post-transplant in 426 patients with a combined 31,125 tacrolimus levels. Included in the outcomes study were 220 patients, of whom 51 developed C1q-binding de novo donor-specific antibodies. De novo donor-specific antibody formers had higher intrapatient variability, with a median of 38% (interquartile range, 28%-48%) compared with 28% (interquartile range, 20%-38%) for nondonor-specific antibody formers (P<0.001). Patients with high tacrolimus intrapatient variability (coefficient of variation >30%) had higher risk of de novo donor-specific antibody formation (hazard ratio, 5.35; 95% confidence interval, 2.45 to 11.68). Patients in the top quartile of tacrolimus intrapatient variability (coefficient of variation >41%) had the strongest association with C1q-binding de novo donor-specific antibody formation (hazard ratio, 11.81; 95% confidence interval, 4.76 to 29.27). CONCLUSIONS High tacrolimus intrapatient variability was strongly associated with de novo donor-specific antibody formation.
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Affiliation(s)
- Kim H. Piburn
- Division of Nephrology, Department of Pediatrics, Stanford University, Palo Alto, California
| | - Vaka K. Sigurjonsdottir
- Division of Nephrology, Department of Pediatrics, Stanford University, Palo Alto, California,Division of Nephrology, Internal Medicine and Emergency Services, Landspitali–The National University Hospital of Iceland, Reykjavik, Iceland,Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland
| | - Olafur S. Indridason
- Division of Nephrology, Internal Medicine and Emergency Services, Landspitali–The National University Hospital of Iceland, Reykjavik, Iceland
| | - Lynn Maestretti
- Pediatric Kidney Transplant Program, Division of Nephrology, Department of Pediatrics, Lucile Packard Children’s Hospital Stanford, Palo Alto, California
| | - Mary Victoria Patton
- Pediatric Kidney Transplant Program, Division of Nephrology, Department of Pediatrics, Lucile Packard Children’s Hospital Stanford, Palo Alto, California
| | - Anne McGrath
- Pediatric Kidney Transplant Program, Division of Nephrology, Department of Pediatrics, Lucile Packard Children’s Hospital Stanford, Palo Alto, California
| | - Runolfur Palsson
- Division of Nephrology, Internal Medicine and Emergency Services, Landspitali–The National University Hospital of Iceland, Reykjavik, Iceland,Medicine, School of Health Sciences, University of Iceland, Reykjavik, Iceland
| | - Amy Gallo
- Division of Abdominal Transplantation, Department of Surgery, Stanford University, Palo Alto, California
| | - Abanti Chaudhuri
- Division of Nephrology, Department of Pediatrics, Stanford University, Palo Alto, California
| | - Paul C. Grimm
- Division of Nephrology, Department of Pediatrics, Stanford University, Palo Alto, California
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18
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Duncan-Park S, Danziger-Isakov L, Armstrong B, Williams N, Odim J, Shemesh E, Sweet S, Annunziato R. Posttraumatic stress and medication adherence in pediatric transplant recipients. Am J Transplant 2022; 22:937-946. [PMID: 34837457 PMCID: PMC8897237 DOI: 10.1111/ajt.16896] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 11/02/2021] [Accepted: 11/04/2021] [Indexed: 01/25/2023]
Abstract
Adolescent transplant recipients may encounter a range of potentially traumatic events (PTEs) pre- and posttransplant, yet little is known about the relationship between posttraumatic stress symptoms (PTSS) and medication adherence in this population. In the present study, adolescent recipients and caregivers completed psychosocial questionnaires at enrollment. Outpatient tacrolimus trough level data were collected over 1 year to calculate the Medication Level Variability Index (MLVI), a measure of medication adherence. Nonadherence (MLVI ≥2) was identified in 34.8% of patients, and most (80.7%) reported ≥1 PTE exposure. Levels of PTSS indicating likely posttraumatic stress disorder (PTSD) were endorsed by 9.2% of patients and 43.7% of caregivers. PTSS and MLVI were significantly correlated in the liver subgroup (r = .30, p = .04). Hierarchical multivariable linear regression analyses revealed overall patient PTSS were significantly associated with QoL (p < .001). PTEs are common in adolescent recipients; a minority may meet criteria for PTSD. PTSS screening to identify nonadherence risk requires further investigation and addressing PTSS may improve QoL. Caregivers appear at greater risk for PTSD and may require their own supports. The study was approved by each participating center's Institutional Review Board.
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Affiliation(s)
- Sarah Duncan-Park
- Icahn School of Medicine at Mount Sinai, NY, NY
- Fordham University, Bronx, NY
| | | | | | | | | | | | | | - Rachel Annunziato
- Icahn School of Medicine at Mount Sinai, NY, NY
- Fordham University, Bronx, NY
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19
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Review and Evaluation of mHealth Apps in Solid Organ Transplantation: Past, Present, and Future. Transplant Direct 2022; 8:e1298. [PMID: 35368987 PMCID: PMC8966961 DOI: 10.1097/txd.0000000000001298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 12/14/2021] [Accepted: 01/04/2022] [Indexed: 11/26/2022] Open
Abstract
With the rapid and widespread expansion of smartphone availability and usage, mobile health (mHealth) has become a viable multipurpose treatment medium for the US healthcare system.
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20
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González-Vílchez F, Crespo-Leiro MG, Delgado-Jiménez J, Pérez-Villa F, Segovia-Cubero J, Díaz-Molina B, Mirabet-Pérez S, Arizón del Prado JM, Blasco-Peiró T, Martínez-Sellés M, Almenar-Bonet L, Garrido-Bravo I, Rábago G, Vázquez de Prada JA. Impacto de la variabilidad intrapaciente en la concentración sanguínea de anticalcineurínicos en los resultados del trasplante cardiaco. Rev Esp Cardiol 2022. [DOI: 10.1016/j.recesp.2021.02.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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21
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González-Vílchez F, Crespo-Leiro MG, Delgado-Jiménez J, Pérez-Villa F, Segovia-Cubero J, Díaz-Molina B, Mirabet-Pérez S, Arizón Del Prado JM, Blasco-Peiró T, Martínez-Sellés M, Almenar-Bonet L, Garrido-Bravo I, Rábago G, Vázquez de Prada JA. Impact of intrapatient blood level variability of calcineurin inhibitors on heart transplant outcomes. REVISTA ESPANOLA DE CARDIOLOGIA (ENGLISH ED.) 2022; 75:129-140. [PMID: 33744197 DOI: 10.1016/j.rec.2021.02.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 02/08/2021] [Indexed: 06/12/2023]
Abstract
INTRODUCTION AND OBJECTIVES Intrapatient blood level variability (IPV) of calcineurin inhibitors has been associated with poor outcomes in solid-organ transplant, but data for heart transplant are scarce. Our purpose was to ascertain the clinical impact of IPV in a multi-institutional cohort of heart transplant recipients. METHODS We retrospectively studied patients aged ≥18 years, with a first heart transplant performed between 2000 and 2014 and surviving≥ 1 year. IPV was assessed by the coefficient of variation of trough levels from posttransplant months 4 to 12. A composite of rejection or mortality/graft loss or rejection and all-cause mortality/graft loss between years 1 to 5 posttransplant were analyzed by Cox regression analysis. RESULTS The study group consisted of 1581 recipients (median age, 56 years; women, 21%). Cyclosporine immediate-release tacrolimus and prolonged-release tacrolimus were used in 790, 527 and 264 patients, respectively. On multivariable analysis, coefficient of variation> 27.8% showed a nonsignificant trend to association with 5-year rejection-free survival (HR, 1.298; 95%CI, 0.993-1.695; P=.056) and with 5-year mortality (HR, 1.387; 95%CI, 0.979-1.963; P=.065). Association with rejection became significant on analysis of only those patients without rejection episodes during the first year posttransplant (HR, 1.609; 95%CI, 1.129-2.295; P=.011). The tacrolimus-based formulation had less IPV than cyclosporine and better results with less influence of IPV. CONCLUSIONS IPV of calcineurin inhibitors is only marginally associated with mid-term outcomes after heart transplant, particularly with the tacrolimus-based immunosuppression, although it could play a role in the most stable recipients.
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Affiliation(s)
| | - María G Crespo-Leiro
- Servicio de Cardiología, Complexo Hospitalario Universitario A Coruña, A Coruña, Spain
| | - Juan Delgado-Jiménez
- Servicio Cardiología y Fundación Investigación Hospital Universitario 12 de Octubre, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain
| | - Félix Pérez-Villa
- Servicio de Cardiología, Hospital Clínic Universitari, Barcelona, Spain
| | - Javier Segovia-Cubero
- Servicio de Cardiología, Hospital Universitario Puerta de Hierro-Majadahonda, Majadahonda, Madrid, Spain
| | - Beatriz Díaz-Molina
- Servicio de Cardiología, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain
| | - Sonia Mirabet-Pérez
- Servei de Cardiologia, Hospital Universitari Santa Creu i Sant Pau, Barcelona, Spain
| | | | - Teresa Blasco-Peiró
- Servicio de Cardiología, Hospital Universitario Miguel Servet, Zaragoza, Spain
| | - Manuel Martínez-Sellés
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain; Servicio de Cardiología, Hospital Universitario Gregorio Marañón, Madrid, Spain; Facultad de Medicina, Universidad Europea, Madrid, Spain; Facultad de Medicina, Universidad Complutense, Madrid, Spain
| | - Luis Almenar-Bonet
- Servicio de Cardiología, Hospital Universitario y Politécnico La Fe, Valencia, Spain
| | - Iris Garrido-Bravo
- Servicio de Cardiología, Hospital Universitario Virgen de la Arrixaca, El Palmar, Murcia, Spain
| | - Gregorio Rábago
- Servicio de Cirugía Cardiaca, Clínica Universitaria de Navarra, Pamplona, Spain
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22
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Baghai Arassi M, Gauche L, Schmidt J, Höcker B, Rieger S, Süsal C, Tönshoff B, Fichtner A. Association of intraindividual tacrolimus variability with de novo donor-specific HLA antibody development and allograft rejection in pediatric kidney transplant recipients with low immunological risk. Pediatr Nephrol 2022; 37:2503-2514. [PMID: 35166920 PMCID: PMC9395307 DOI: 10.1007/s00467-022-05426-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 11/24/2021] [Accepted: 12/13/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND Tacrolimus (Tac) intraindividual variability (TacIPV) in pediatric kidney transplant patients is only poorly understood. We investigated the impact of TacIPV on de novo donor-specific HLA antibodies (dnDSA) development and allograft rejection in Caucasian pediatric recipients of a living or deceased donor kidney with low immunological risk. METHODS This was a single-center retrospective study including 48 pediatric kidney transplant recipients. TacIPV was calculated based on coefficient of variation (CV%) 6-12 months posttransplant. TacIPV cutoff was set at the median (25%). Outcome parameters were dnDSA development and rejection episodes. RESULTS In total, 566 Tac levels were measured with median 11.0 (6.0-17.0) measurements per patient. The cutoff of 25% corresponded to the median CV% in our study cohort (25%, IQR 18-35%) and was comparable to cutoffs determined by receiver operating characteristic (ROC) curve analysis. High TacIPV was associated with higher risk of dnDSA development (HR 3.4, 95% CI 1.0-11.1, P = 0.047; Kaplan-Meier analysis P = 0.018) and any kind of rejection episodes (HR 4.1, 95% CI 1.1-14.8, P = 0.033; Kaplan-Meier analysis P = 0.010). There was a clear trend towards higher TacIPV below the age of 6 years. TacIPV (CV%) was stable over time. A TacIPV (CV%) cutoff of 30% or IPV quantification by mean absolute deviation (MAD) showed comparable results. CONCLUSIONS High TacIPV is associated with an increased risk of dnDSA development and rejection episodes > year 1 posttransplant even in patients with low immunological risk profile. Therefore, in patients with high TacIPV, potential causes should be addressed, and if not resolved, changes in immunosuppressive therapy should be considered. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Affiliation(s)
- Maral Baghai Arassi
- Department of Pediatrics I, University Children's Hospital Heidelberg, Heidelberg, Germany. .,Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
| | - Laura Gauche
- Department of Pediatrics I, University Children’s Hospital Heidelberg, Heidelberg, Germany
| | - Jeremy Schmidt
- Department of Pediatrics I, University Children’s Hospital Heidelberg, Heidelberg, Germany
| | - Britta Höcker
- Department of Pediatrics I, University Children’s Hospital Heidelberg, Heidelberg, Germany
| | - Susanne Rieger
- Department of Pediatrics I, University Children’s Hospital Heidelberg, Heidelberg, Germany
| | - Caner Süsal
- Institute of Immunology, Transplantation Immunology, University Hospital Heidelberg, Heidelberg, Germany
| | - Burkhard Tönshoff
- Department of Pediatrics I, University Children’s Hospital Heidelberg, Heidelberg, Germany
| | - Alexander Fichtner
- Department of Pediatrics I, University Children’s Hospital Heidelberg, Heidelberg, Germany
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23
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Urzykowska A, Piątosa B, Grycuk U, Kowalewski G, Kułaga Z, Grenda R. Evaluation of Cumulative Effect of Standard Triple Immunosuppression on Prevention of De Novo Donor Specific Antibodies (dnDSA) Production in Children after Kidney Transplantation—A Retrospective and Prospective Study. CHILDREN 2021; 8:children8121162. [PMID: 34943360 PMCID: PMC8700537 DOI: 10.3390/children8121162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 12/06/2021] [Accepted: 12/07/2021] [Indexed: 11/23/2022]
Abstract
De novo Donor Specific Antibodies (dnDSA) are associated with inferior graft outcomes. Standard immunosuppression is expected to prevent dnDSA production in low-risk patients. We have evaluated a cumulative effect of a triple immunosuppression (CNI/MMF/Pred), as well as TAC concentration and coefficient of variation on the incidence of dnDSA production. Overall, 67 transplanted patients were evaluated in retrospective (dnDSA for-cause; n = 29) and prospective (dnDSA by protocol; n = 38) groups. In the retrospective group, the eGFR value at first dnDSA detection (median interval—4.0 years post-transplant) was 41 mL/min/1.73 m2; 55% of patients presented biopsy-proven cAMR, and 41% lost the graft within next 2.4 years. Patients from the prospective group presented 97% graft survival and eGFR of 76 mL/min/1.73 m2 at 2 years follow-up, an overall incidence of 21% of dnDSA and 18% of acute (T cell) rejection. None of the patients from the prospective group developed cAMR. Median value of Vasudev score within 2 years of follow-up was not significantly higher in dsDSA negative patients, while median value of TAC C0 > 1–24 months post-transplant was 7.9 in dnDSA negative vs. 7.1 ng/mL in dnDSA positive patients (p = 0.008). Conclusion: dnDSA-negative patients presented a higher exposure to tacrolimus, while not to the combined immunosuppression.
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Affiliation(s)
- Agnieszka Urzykowska
- Department of Nephrology, Kidney Transplantation & Hypertension, Children’s Memorial Health Institute, 04-730 Warsaw, Poland;
| | - Barbara Piątosa
- Histocompatibility Laboratory, Children’s Memorial Health Institute, 04-730 Warsaw, Poland; (B.P.); (U.G.)
| | - Urszula Grycuk
- Histocompatibility Laboratory, Children’s Memorial Health Institute, 04-730 Warsaw, Poland; (B.P.); (U.G.)
| | - Grzegorz Kowalewski
- Department of Surgery and Organ Transplantation, Children’s Memorial Health Institute, 04-730 Warsaw, Poland;
| | - Zbigniew Kułaga
- Department of Public Health, Children’s Memorial Health Institute, 04-730 Warsaw, Poland;
| | - Ryszard Grenda
- Department of Nephrology, Kidney Transplantation & Hypertension, Children’s Memorial Health Institute, 04-730 Warsaw, Poland;
- Correspondence:
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24
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Hwang YH, Kim H, Min K, Yang J. Tacrolimus trough levels in kidney transplant recipients. BMC Nephrol 2021; 22:405. [PMID: 34876046 PMCID: PMC8650372 DOI: 10.1186/s12882-021-02622-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 11/15/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND It is very important that kidney transplant recipients (KTRs) take immunosuppressive drugs to prevent graft rejection. This study aimed to identify the tacrolimus trough levels (TTL)-mean, TTL-standard deviation (SD), and TTL- coefficient of variation (CV) as well as factors affecting these values over a 2-year period in clinically stable patients > 5 years after kidney transplantation (KT). METHODS This retrospective study analyzed data from 248 adult outpatients > 5 years after KT. Medical chart data, including TTL, graft rejection, and tacrolimus dose change during a 2-year period, between January 2017 and December 2018, were collected. Multivariable regression analyses were conducted to determine the factors influencing the TTL-mean, TTL-SD, and TTL-CV. RESULTS The TTL-mean, TTL-SD, and TTL-CV were 6.00 ± 1.07 ng/mL, 1.51 ± 1.09 ng/mL, and 0.25 ± 0.14, respectively. The TTL-mean, TTL-SD, and TTL-CV did not differ according to sex, type of donor, retransplant, pretransplant kidney disease, body mass index, or posttransplant time; hence, they are stable in kidney transplant recipients > 5 years after KT. The higher the TTL-mean, the higher the TTL-SD. Age and the TTL-SD significantly predicted the TTL-mean (p < .001). Tacrolimus dose change and the TTL-mean significantly predicted the TTL-SD (p < .001). Tacrolimus dose change significantly predicted the TTL-CV (p = .008). CONCLUSION In clinically stable KTRs, TTL-SD and TTL-CV change sensitively in relation to tacrolimus dose changes. Therefore, changes in TTL-SD and TTL-CV in stable KTRs with no tacrolimus dose change require medical interest and attention.
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Affiliation(s)
- Young Hui Hwang
- Department of Nursing, College of Medicine, University of Ulsan, Ulsan, South Korea
| | - Hyunjung Kim
- Divison of Nursing & Research Institute of Nursing Science, Hallym University, 1 Hallymdaehak-gil, Chuncheon, Gangwon-do, 24252, South Korea.
| | - Kyungok Min
- Transplant Center, Department of Nursing, Seoul National University Hospital, Seoul, South Korea
| | - Jaeseok Yang
- Division of Nephrology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
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25
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Chandran MM, Blanchette E, Goebel J, Bock M. Impact of once-daily ER-Tac on trough concentration variability in a stable AYA renal transplant recipient cohort. Pediatr Transplant 2021; 25:e14036. [PMID: 34003550 DOI: 10.1111/petr.14036] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Revised: 04/21/2021] [Accepted: 04/22/2021] [Indexed: 01/14/2023]
Abstract
BACKGROUND Successful renal transplantation requires complex medication regimens that rely on strict adherence to be effective. Variability in immunosuppression exposure, specifically tacrolimus, is associated with poor allograft outcomes. Wide intra-patient variability of tacrolimus trough concentrations (Vtac) is likely, in part, attributable to regimen complexity and poor medication adherence. Once-daily tacrolimus formulations create opportunity to simplify therapeutic regimens, and this study aims to evaluate their impact on Vtac and ultimately transplant outcomes. METHODS This retrospective cohort study investigated stable (AYA) renal transplant recipients converted from (IR-Tac) to (ER-Tac). Subjects served as their own controls. Vtac was assessed by measuring the (SD) of serial tacrolimus trough concentrations prior to and at four time points post-conversion to ER-Tac over 24-month follow-up. Secondary outcome measures included graft function, infection rates, and effect on modifiable treatment-related factors. RESULTS Twenty-eight AYA subjects were converted from IR-Tac to ER-Tac. Vtac significantly improved following conversion and was sustained for 24 months (Vtac0 2.32 vs. Vtac24 1.11, p .017). Renal function remained stable, and (BPAR) rates were modest (14%). Mean pill burden was reduced by 15%, and 42.9% of subjects achieved a once-daily medication regimen. CONCLUSIONS Conversion from IR-Tac to ER-Tac in this AYA population significantly improved Vtac with sustained effect over 2 years. This effect is likely attributable in part to simplification of the medication regimen and presumably improved medication adherence. Such conversion does not appear to compromise graft function for at least 2 years post-conversion.
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Affiliation(s)
| | - Eliza Blanchette
- Department of Pediatric Nephrology, Children's Hospital Colorado, Aurora, CO, USA
| | - Jens Goebel
- Department of Pediatric Nephrology, Helen DeVos Children's Hospital, Grand Rapids, MI, USA
| | - Margret Bock
- Department of Pediatric Nephrology, Children's Hospital Colorado, Aurora, CO, USA
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26
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Lang S, Sharma A, Foster B, Gibson IW, Ho J, Nickerson P, Wishart D, Blydt-Hansen T. Age and sex determine conversion from immediate-release to extended-release tacrolimus in a multi-center cohort of Canadian pediatric renal transplant recipients. Pediatr Transplant 2021; 25:e13959. [PMID: 33368914 DOI: 10.1111/petr.13959] [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: 09/25/2020] [Revised: 11/11/2020] [Accepted: 12/08/2020] [Indexed: 11/27/2022]
Abstract
ER-Tac, taken once per day, is associated with improved adherence. This study examined the potential patient and clinical factors that influence clinicians to convert pediatric patients from immediate-release to ER-Tac. This prospective multi-center observational study followed Canadian pediatric kidney transplant recipients up to 5 years post-transplant. Cox Proportional Hazards Regression was used to examine the influence of factors on conversion to ER-Tac. Sixty-six participants were included in this analysis. For every additional year of age at the time of transplant, the likelihood of conversion was more than doubled (HR 2.54, CI 1.83, 3.54, P < 0.001). The impact of age reduced by three percent for every month after transplant (HR 0.97, CI 0.95, 0.98, P < 0.001). Girls were more likely to be converted than boys (HR 3.78, CI 1.35, 10.6, P 0.01). Adherence measures (MAM-MM and tacrolimus trough variability), individual barriers to adherence, renal function, HLA mismatch, and rejection were not significant predictors of conversion in the final regression model. ER-Tac was preferentially prescribed to older age and female patients. Female sex and adolescence are both associated with worse graft outcomes, but we found no link between individualized markers of adherence/graft risk and conversion. Clinicians appeared to be using demographic features to distinguish patients at perceived higher risk and converted accordingly, without a case-by-case evaluation of who is more susceptible to poor outcomes.
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Affiliation(s)
- Samantha Lang
- Department of Medicine, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Atul Sharma
- Biostatistical Consulting Unit, George and Fay Yee Center for Healthcare Innovation, University of Manitoba, Winnipeg, MB, Canada
| | - Beth Foster
- Montreal Children's Hospital Research Institute, McGill University Health Centre, Montreal, QC, Canada.,Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, QC, Canada
| | - Ian W Gibson
- Pathology, University of Manitoba, Winnipeg, MB, Canada
| | - Julie Ho
- Department of Internal Medicine, Section of Nephrology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.,Manitoba Centre for Proteomics & Systems Biology, Winnipeg, MB, Canada
| | - Peter Nickerson
- Department of Internal Medicine, Section of Nephrology, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.,Transplant/Immunology Lab, University of Manitoba, Winnipeg, MB, Canada
| | - David Wishart
- Computing Science, University of Alberta, Edmonton, AB, Canada.,The Metabolomics Innovation Center, Edmonton, AB, Canada
| | - Tom Blydt-Hansen
- Pediatric Nephrology, The University of British Columbia, Vancouver, BC, Canada
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27
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Krause AV, Bertram A, Nöhre M, Bauer-Hohmann M, Schiffer M, de Zwaan M. Use of an electronic medication monitoring device to estimate medication adherence in kidney transplant patients. Transl Behav Med 2021; 11:842-851. [PMID: 33710349 DOI: 10.1093/tbm/ibaa122] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Electronic medication monitoring devices (EMD) have been used as a gold standard for assessing medication adherence. We used a wireless EMD (SimpleMed+), assessed its usability in patients after kidney transplantation (KTx), evaluated adherence, and analyzed concordance with other adherence measures. Fifty-five patients (53% female, mean age 46 years) at least 6 months after KTx agreed to use the EMD over a period of 8 weeks. Self-reported adherence was measured with the BAASIS, and immunosuppressant trough level variability was assessed prior to and again during the study period. Fourteen patients stopped using the EMD or were low users (<70%). These non-completers reported that using the EMD would interfere with their daily activities. Taking-adherence of the completers was high with 98.3% (±1.9) over the entire study period. Timing-adherence was somewhat lower (94.6% ± 7.9) and decreased during the second half of the study. We found statistically significant correlations between EMD results and self-reported adherence with moderate effect sizes, but no significant association with trough level variability. The low usage of the EMD supports the need to assess the practicability of an EMD before applying it in research and clinical routine. Taking- and timing-adherence of KTx patients using the EMD was satisfactory. Self-reported adherence might be a good enough estimate of medication adherence.
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Affiliation(s)
- Anna Viktoria Krause
- Department of Psychosomatic Medicine and Psychotherapy, Hannover Medical School, Hanover, Germany.,Integrated Research and Treatment Center Transplantation (IFB-Tx), Hanover, Germany
| | - Anna Bertram
- Integrated Research and Treatment Center Transplantation (IFB-Tx), Hanover, Germany.,Department of Nephrology and Hypertension, Hannover Medical School, Hanover, Germany.,Department of Nephrology, Angiology and Rheumatology, KRH Regional Hospital Hannover Siloah, Hanover, Germany
| | - Mariel Nöhre
- Department of Psychosomatic Medicine and Psychotherapy, Hannover Medical School, Hanover, Germany
| | - Maximilian Bauer-Hohmann
- Department of Psychosomatic Medicine and Psychotherapy, Hannover Medical School, Hanover, Germany
| | - Mario Schiffer
- Department of Nephrology and Hypertension, Hannover Medical School, Hanover, Germany.,Department of Nephrology and Hypertension, University Hospital Erlangen, Erlangen, Germany
| | - Martina de Zwaan
- Department of Psychosomatic Medicine and Psychotherapy, Hannover Medical School, Hanover, Germany
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Herblum J, Dacouris N, Huang M, Zaltzman J, Prasad GVR, Nash M, Chen L. Retrospective Analysis of Tacrolimus Intrapatient Variability as a Measure of Medication Adherence. Can J Kidney Health Dis 2021; 8:20543581211021742. [PMID: 34188946 PMCID: PMC8209833 DOI: 10.1177/20543581211021742] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Accepted: 04/26/2021] [Indexed: 11/16/2022] Open
Abstract
Background: Increased intrapatient variability (IPV) in tacrolimus levels is associated with graft rejection, de novo donor-specific antibodies, and graft loss. Medication nonadherence may be a significant contributor to high IPV. Objective: The objective of this study is to determine the utility of tacrolimus IPV in detecting nonadherence by examining the relationship between self-reported adherence and tacrolimus coefficient of variability (COV), a measure of IPV. Design: Retrospective cohort study. Setting: St. Michael’s Hospital, Toronto, Ontario. Patients: All patients who were at least 1-year post-kidney transplant as of March 31, 2019, prescribed tacrolimus as an immunosuppressant and had a self-reported adherence status. Patients were excluded from the primary analysis of examining the correlation between COV and self-reported adherence if they lacked a calculatable COV. Measurements: Self-reported adherence, COV, demographic data, transplant, and medication history. Methods: A modified Basel Assessment of Adherence to Immunosuppressive Medications Scale (BAASIS) administered by healthcare professionals to assess self-reported adherence was used. The COV of tacrolimus trough levels was calculated and its correlation to BAASIS response was noted. The median COV was used as a cutoff to examine the characteristics of patients deemed “high COV” and “low COV.” Results: A total of 591 patients fit the initial criteria; however, only 525 had a recent calculatable COV. Overall, 92.38% of the population were adherent by self-report. Primary analysis identified a COV of 25.2% and 29.6% in self-reported adherent and nonadherent patients, respectively, though the result was not significant (P = .2). Secondary analyses showed a significant correlation between younger age at transplant and at the time of adherence self-reporting with nonadherence (P = .01). In addition, there was a strong correlation between those nonadherent with routine post-transplant blood work and younger age (P < .01). Limitations: The limitations included modified nonvalidated BAASIS questionnaire, social desirability bias, BAASIS only administered in English, and patients with graft failure not active in clinic not being captured. Conclusions: The COV should not be used as the sole method for determining medication adherence. However, COV may have some utility in capturing individuals who are not adherent to their blood work or patients who are having a poor response to tacrolimus and should be switched to another medication.
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Affiliation(s)
- Jordana Herblum
- Keenan Research Summer Student Program, St. Michael's Hospital, Toronto, ON, Canada
| | - Niki Dacouris
- Kidney and Metabolism Program, Unity Health Toronto, ON, Canada
| | - Michael Huang
- Kidney and Metabolism Program, Unity Health Toronto, ON, Canada
| | - Jeffrey Zaltzman
- Division of Nephrology, Department of Medicine, St. Michael's Hospital, Toronto, ON, Canada
| | - G V Ramesh Prasad
- Division of Nephrology, Department of Medicine, St. Michael's Hospital, Toronto, ON, Canada
| | - Michelle Nash
- Kidney Research Program, St. Michael's Hospital, Toronto, ON, Canada
| | - Lucy Chen
- Kidney Research Program, St. Michael's Hospital, Toronto, ON, Canada
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Abstract
Tacrolimus was discovered in 1984 and entered clinical use shortly thereafter, contributing to successful solid organ transplantation across the globe. In this review, we cover development of tacrolimus, its evolving clinical utility, and issues affecting its current usage. Since earliest use of this class of immunosuppressant, concerns for calcineurin-inhibitor toxicity have led to efforts to minimize or eliminate these agents in clinical regimens but with limited success. Current understanding of the role of tacrolimus focuses more on its efficacy in preventing graft rejection and graft loss. As we enter the fourth decade of tacrolimus use, newer studies utilizing novel combinations (as with the mammalian target of rapamycin inhibitor, everolimus, and T-cell costimulation blockade with belatacept) offer potential for enhanced benefits.
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Affiliation(s)
- Song C Ong
- Department of Medicine, Division of Nephrology, University of Alabama at Birmingham, Birmingham, AL
| | - Robert S Gaston
- Department of Medicine, Division of Nephrology, University of Alabama at Birmingham, Birmingham, AL
- CTI Clinical Trial and Consulting, Inc., Covington, KT
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30
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Schumacher L, Leino AD, Park JM. Tacrolimus intrapatient variability in solid organ transplantation: A multiorgan perspective. Pharmacotherapy 2020; 41:103-118. [PMID: 33131078 DOI: 10.1002/phar.2480] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 09/21/2020] [Accepted: 09/26/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND Tacrolimus therapy in solid organ transplant (SOT) recipients is challenging due to its narrow therapeutic window and pharmacokinetic variability both between patients and within a single patient. Intrapatient variability (IPV) of tacrolimus trough concentrations has become a novel marker of interest for predicting transplant outcomes. The purpose of this review is to evaluate the association of tacrolimus IPV with graft and patient outcomes and identify interventions to improve IPV in SOT recipients. METHODS A systematic review of the literature was performed using PubMed and Embase from database inception to September 20, 2020. Studies were eligible only if they evaluated an association between tacrolimus IPV and transplant outcomes. Both pediatric and adult studies were included. Measures of variability were limited to standard deviation, coefficient of variation, and time in therapeutic range. RESULTS Forty-four studies met the inclusion criteria. Studies were published between 2008 and 2020 and were observational in nature. Majority of data were published in adult kidney transplant recipients and identified an association with rejection, de novo donor specific antibody (dnDSA) formation, graft loss, and patient survival. Evaluation of IPV-directed interventions was limited to small preliminary studies. CONCLUSIONS High tacrolimus IPV has been associated with poor outcomes including acute rejection, dnDSA formation, graft loss, and patient mortality in SOT recipients. Future research should prospectively explore IPV-directed interventions to improve transplant outcomes.
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Affiliation(s)
| | - Abbie D Leino
- Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA
| | - Jeong M Park
- Department of Pharmacy, Michigan Medicine, Ann Arbor, MI, USA.,Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA
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31
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Chen CC, Lin WC, Lee CY, Yang CY, Tsai MK. Two-year protocol biopsy after kidney transplantation in clinically stable recipients - a retrospective study. Transpl Int 2020; 34:185-193. [PMID: 33152140 DOI: 10.1111/tri.13785] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 08/14/2020] [Accepted: 11/02/2020] [Indexed: 12/25/2022]
Abstract
The idea of protocol biopsy is to detect subclinical pathologies, including rejection, recurrent disease, or infection for early intervention and adjustment of immunosuppressants. Nevertheless, it is not adopted by most clinicians because of its low yield rate and uncertain long-term benefits. This retrospective study evaluated the impact of protocol biopsy on renal function and allograft survival. A two-year protocol biopsy was proposed for 190 stable patients; 68 of them accepted [protocol biopsy (PB) group], while 122 did not [nonprotocol biopsy (NPB) group]. The rejection diagnosis was made in 13 patients by protocol biopsy, and 11 of them had borderline rejection. In the following 5 years, graft survival was better in the PB group than in the NPB group (P = 0.0143). A total of 4 and 17 patients in the PB and NPB groups, respectively, had rejection events proven by indication biopsy. Renal function was better preserved in the PB group than in the NPB group (P = 0.0107) for patients with rejection events. Nevertheless, the survival benefit disappeared by a longer follow-up period (12-year, P = 0.2886). In conclusion, 2-year protocol biopsy detects subclinical pathological changes in rejection and preserves renal function by early intervention so as to prolong graft survival within 5 years.
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Affiliation(s)
- Chien-Chia Chen
- Division of General Surgery, Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
| | - Wei-Chou Lin
- Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan
| | - Chih-Yuan Lee
- Division of General Surgery, Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
| | - Ching-Yao Yang
- Division of General Surgery, Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
| | - Meng-Kun Tsai
- Division of General Surgery, Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.,Division of General Surgery, Department of Surgery, National Taiwan University Hospital Hsinchu Branch, Hsinchu, Taiwan
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32
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Chu MC, Smith PJ, Reynolds JM, Palmer SM, Snyder LD, Gray AL, Blumenthal JA. Depression, Immunosuppressant Levels, and Clinical Outcomes in Postlung Transplant Recipients. Int J Psychiatry Med 2020; 55:421-436. [PMID: 32052665 DOI: 10.1177/0091217420906637] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Posttransplant depression has been linked to increased risk for adverse outcomes in lung transplant patients. Maintaining target serum immunosuppressant levels is also essential for optimal lung transplant clinical outcome and may be a crucial predictor of outcomes. Because depression could affect medication nonadherence, resulting in out-of-range immunosuppressant levels, we examined the relationship between posttransplant depression, immunosuppressant medication trough level variability, indexed by out-of-range values on clinical outcomes and coefficient of variability, and clinical outcomes. METHOD A consecutive series of 236 lung transplant recipients completed the Center for Epidemiological Studies-Depression two-month posttransplant. Immunosuppressant trough levels (i.e., tacrolimus or cyclosporine) within the range of individualized immunosuppressant targets were obtained at three-, six-, nine-month follow-up clinic visits. Clinical outcomes including hospitalizations and mortality were obtained from medical records. RESULTS Fourteen percent of patients were classified as depressed (Center for Epidemiological Studies-Depression ≥16), 144 (61%) of patients had at least 25% out-of-range immunosuppressant values, and the average coefficient of variability was 36%. Over a median of 2.6 years (interquartile range = 1.2), 32 participants died (14%) and 144 (61%) had at least one unplanned, transplant-related hospitalization. Both depression (hazard ratio = 1.45 (1.19, 1.76), p < . 01) and immunosuppressant variation (immunosuppressant out-of-range: hazard ratio = 1.41 (1.10, 1.81), p < .01) independently predicted more frequent hospitalizations and higher mortality. CONCLUSIONS Early posttransplant depression was associated with significantly worse clinical outcomes. While immunosuppressant level variability is also related to adverse outcomes, such variability does not account for increased risk observed with depression.
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Affiliation(s)
- Michael C Chu
- Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA
| | - Patrick J Smith
- Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA
| | - John M Reynolds
- Department of Medicine, Duke University Medical Center, Durham, NC, USA
| | - Scott M Palmer
- Department of Medicine, Duke University Medical Center, Durham, NC, USA
| | - Laurie D Snyder
- Department of Medicine, Duke University Medical Center, Durham, NC, USA
| | - Alice L Gray
- Department of Medicine, Duke University Medical Center, Durham, NC, USA
| | - James A Blumenthal
- Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA
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33
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Lieb M, Weyand M, Seidl M, Erim Y. Prospective single-centre clinical observational study on electronically monitored medication non-adherence, its psychosocial risk factors and lifestyle behaviours after heart transplantation: a study protocol. BMJ Open 2020; 10:e038637. [PMID: 33033024 PMCID: PMC7542932 DOI: 10.1136/bmjopen-2020-038637] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
INTRODUCTION In heart transplant recipients (HTRs), non-adherence (NA) to immunosuppressive (IS) medication and to recommended lifestyle behaviours are a common phenomenon and associated with higher risk of allograft rejection, organ loss and mortality. Risk factors for NA are highly diverse and still insufficiently researched. Precise measures of NA and an accurate understanding of its aetiology are of undisputable importance to detect patients at risk and intervene accordingly. The aim of this study is to assess the accuracy and concordance of different measures for NA as well as to determine potential risk factors. METHODS AND ANALYSIS This is a single-centre prospective observational trial. HTRs who are at least aged 18 are no less than 6 months post-transplant and receive tacrolimus (Prograf or Advagraf), cyclosporine (Sandimmun) or everolimus (Certican) as their prescribed IS medication are eligible for participation. We only include patients during the phase of medication implementation. At study enrolment, we assess depression, health-related quality of life, self-efficacy, social support, attachment, experiences and attitudes towards IS medication, emotional responses after transplantation, satisfaction with information about IS medication and perceptions and beliefs about medications. We further ask patients to rate their lifestyle behaviours concerning alcohol, smoking, diet, physical activity, sun protection and appointment keeping via questionnaires. Three different measurement methods for NA are applied at T0: self-reports, physician's estimates and IS trough levels. NA is monitored prospectively using an electronic multicompartment pillbox (MEMS, VAICA) over a 3-month period. Meanwhile, participants receive phone calls every second week to obtain additional self-reports, resulting in a total of seven measurement points. ETHICS AND DISSEMINATION The study was approved by the Clinical Ethics Committee of the University Hospital Erlangen (Friedrich-Alexander-University, Erlangen-Nürnberg). Written informed consent is attained from all participants. The results of this study will be published in peer-reviewed journals and presented at conferences. TRIAL REGISTRATION NUMBER DRKS00020496.
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Affiliation(s)
- Marietta Lieb
- Department of Psychosomatic Medicine and Psychotherapy, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
| | - Michael Weyand
- Department of Cardiac Surgery, University Hospital Erlangen, Erlangen, Germany
| | - Margot Seidl
- Department of Cardiac Surgery, University Hospital Erlangen, Erlangen, Germany
| | - Yesim Erim
- Department of Psychosomatic Medicine and Psychotherapy, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
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34
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Gold A, Tönshoff B, Döhler B, Süsal C. Association of graft survival with tacrolimus exposure and late intra-patient tacrolimus variability in pediatric and young adult renal transplant recipients-an international CTS registry analysis. Transpl Int 2020; 33:1681-1692. [PMID: 32881096 DOI: 10.1111/tri.13726] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 06/30/2020] [Accepted: 08/24/2020] [Indexed: 01/03/2023]
Abstract
Adolescent and young adult age is a high-risk window with an alarmingly increased likelihood of premature kidney graft loss due to immunological rejection. Using the large database of the Collaborative Transplant Study, we analyzed whether a more intense and less variable exposure to tacrolimus could counteract this young age-related enhanced immunoreactivity. Kidney graft recipients aged 12-23 years (n = 964) with a 1-year tacrolimus trough level between 4.0 and 10.9 ng/ml had a 5-year graft survival rate of 85.1%, significantly better than the poor 66.1% rate in patients with a trough level below 4.0 ng/ml who showed a 2.38-fold increased risk of graft loss in the multivariable analysis (P < 0.001). This association was not apparent in young children aged 0-11 years (n = 455) and less pronounced in adults aged 24-34 years (n = 1466). However, an intra-patient variability of tacrolimus (IPV) trough level ≥1.5 at post-transplant years 1 and 2 was associated with an increased graft loss risk in both 12- to 23-year-old and 0- to 11-year-old recipients (P < 0.001 and P = 0.045). Patients with high IPV made up as many as 30% of kidney graft recipients, indicating that a more intense and less variable exposure to tacrolimus could improve graft survival strongly in this high-risk group.
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Affiliation(s)
- Annika Gold
- Department of Pediatrics I, University Children's Hospital Heidelberg, Heidelberg, Germany
| | - Burkhard Tönshoff
- Department of Pediatrics I, University Children's Hospital Heidelberg, Heidelberg, Germany
| | - Bernd Döhler
- Institute of Immunology, University Hospital Heidelberg, Heidelberg, Germany
| | - Caner Süsal
- Institute of Immunology, University Hospital Heidelberg, Heidelberg, Germany
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35
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Lieb M, Hepp T, Schiffer M, Opgenoorth M, Erim Y. Accuracy and concordance of measurement methods to assess non-adherence after renal transplantation - a prospective study. BMC Nephrol 2020; 21:114. [PMID: 32234021 PMCID: PMC7110822 DOI: 10.1186/s12882-020-01781-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Accepted: 03/23/2020] [Indexed: 12/25/2022] Open
Abstract
Background Non-adherence (NA) to immunosuppressants (IS) among renal transplant recipients (RTRs) is associated with higher risk of allograft rejection, graft loss, and mortality. A precise measurement of NA is indispensable, although its prevalence differs greatly depending on the respective measurement methods. The objective of this study was to assess the accuracy and concordance of different measurement methods of NA in patients after renal transplantation. Design and methods This was a single-center prospective observational study. At baseline (T0), NA was measured via physicians’ estimates (PE), self-reports (SR), and tacrolimus trough level variability (CV%) in 78 RTRs. A Visual Analogue Scale (VAS, 0–100%) was applied both for SR and PE. In addition, we used BAASIS© for SR and a 5-point Likert scale for PE. NA was measured prospectively via electronic monitoring (EM, VAICA©) during a three month period. Meanwhile, all participants received phone calls in a two week interval (T1-T6) during which SRs were given. Results Seventy-eight RTRs participated in our study. At t0, NA rates of 6.4%, 28.6%, and 15.4% were found for PE, SR, and CV%, respectively. No correlation was found between these methods. During the study, the percentages of self-reported and electronically monitored adherence remained high, with a minimum mean of 91.2% for the strictest adherence measure (Timing Adherence ±30 min). Our results revealed a moderate to high association between SR and EM. In contrast to PE and CV%, SR significantly predicted electronically monitored adherence. Overall, a decreasing effect of electronically monitored adherence was found for both taking and timing adherence (±2 h, ±30 min) over the course of the study. Discussion The moderate to high concordance of SR and EM suggests that both methods measure NA equally accurately. SR seems to be a method that can adequately depict electronically monitored NA and may represent a good and economical instrument to assess NA in clinical practice. The increased adherence at the beginning of the study and its subsequent decrease suggests an intervention effect. Surveillance of IS intake via EM with intermittent phone calls could improve adherence on a short-term basis. To establish long-term effects, further research is necessary.
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Affiliation(s)
- Marietta Lieb
- Department of Psychosomatic Medicine and Psychotherapy, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), University Hospital of Erlangen, Schwabachanlage 6, 91054, Erlangen, Germany.
| | - Tobias Hepp
- Institute of Medical Informatics, Biometry and Epidemiology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Mario Schiffer
- Department of Nephrology and Hypertension, University Hospital of Erlangen, Erlangen, Germany
| | - Mirian Opgenoorth
- Department of Nephrology and Hypertension, University Hospital of Erlangen, Erlangen, Germany
| | - Yesim Erim
- Department of Psychosomatic Medicine and Psychotherapy, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), University Hospital of Erlangen, Schwabachanlage 6, 91054, Erlangen, Germany
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Tacrolimus variability is associated with de novo donor-specific antibody development in pediatric renal transplant recipients. Pediatr Nephrol 2020; 35:261-270. [PMID: 31732803 DOI: 10.1007/s00467-019-04377-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Revised: 09/04/2019] [Accepted: 09/20/2019] [Indexed: 10/25/2022]
Abstract
BACKGROUND Donor-specific antibody (DSA) is a risk factor for antibody-mediated rejection and shortened graft survival. We investigated the role of intrapatient variability in tacrolimus trough levels on graft outcomes (i.e., de novo DSA, rejection, graft loss) in pediatric renal transplant recipients. METHODS This was a single-center retrospective study which included 38 pediatric renal transplant recipients. Intrapatient tacrolimus variability was defined using the coefficient of variation (CV; SD/Mean × 100) for all levels obtained after 3 months post-transplant. CV cut-points of 30%, 40%, and 50% were used in the analyses. RESULTS The median CV 43.1% (35.0%, 58.6%). Out of 38 patients, 19 (50%) developed de novo DSA. In the logistic regression model, after adjusting for age, rejection history, maintenance immunosuppression, and CV, for every 10% increase in tacrolimus variability, the odds of developing de novo DSA increased by 53% (p = 0.048, CI 1.0005, 1.11). Age at transplant was also an independent risk factor for DSA development; every 1 year increase in age was associated with a 31% increase in the odds of developing DSA (p = 0.03, CI 1.03, 1.67). At a CV cut-point ≥ 30%, higher tacrolimus variability was associated with an increased incidence of allograft rejection (0% vs 42%, < 30 and ≥ 30% respectively, p = 0.07). As there were few graft loss events (n = 4) in our study population, an association could not be determined between tacrolimus variability and graft loss. CONCLUSION Tacrolimus variability and age at transplant were identified as independent risk factors for de novo DSA development. There was an association between tacrolimus variability and rejection in pediatric renal transplant recipients. Adding the assessment of tacrolimus variability to current monitoring methods may be an important step towards improving graft outcomes.
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Bertram A, Fuge J, Suhling H, Tudorache I, Haverich A, Welte T, Gottlieb J. Adherence is associated with a favorable outcome after lung transplantation. PLoS One 2019; 14:e0226167. [PMID: 31846463 PMCID: PMC6917262 DOI: 10.1371/journal.pone.0226167] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Accepted: 11/20/2019] [Indexed: 02/07/2023] Open
Abstract
Non-adherence to therapy is associated with impaired outcome in solid organ allograft recipients. Outcome data are limited after lung transplantation. In a single-center cohort study, adherence was assessed in 427 patients undergoing lung transplantation from 2010 to 2013. Objective criteria of adherence were judged by health care workers on every visit on a five item Likert scale including trough level monitoring, home spirometry and contact with an overall rating of adherence between 0 and 100%. Cut-off values for good vs. suboptimal adherence were defined retrospectively. Primary outcome was allograft survival, secondary outcomes were patient survival, prevalence of chronic lung allograft dysfunction, hospitalizations, renal function and quality of life. Follow-up ended on 31st December 2018. Median adherence was 86% on 6,623 visits, this cut-off was used as a discriminator between good and suboptimal adherers. Patients with good adherence within the first three years showed better 5-year allograft (74% vs. 60%, p = 0.003) and patient survival (79% vs. 64%, p<0.001) and lower prevalence of chronic allograft dysfunction (33% vs. 45%, p = 0.011) after 5 years compared to patients with suboptimal adherence. A multidimensional adherence score proved to be a simple tool to assess adherence in clinical practice. Suboptimal adherence was associated with impaired outcome in lung transplant patients.
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Affiliation(s)
- Anna Bertram
- Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany
- * E-mail:
| | - Jan Fuge
- Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany
- Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Gießen, Germany
| | - Hendrik Suhling
- Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany
- Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Gießen, Germany
| | - Igor Tudorache
- Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany
| | - Axel Haverich
- Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Gießen, Germany
- Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany
| | - Tobias Welte
- Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany
- Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Gießen, Germany
| | - Jens Gottlieb
- Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany
- Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Gießen, Germany
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A Novel, Dose-Adjusted Tacrolimus Trough-Concentration Model for Predicting and Estimating Variance After Kidney Transplantation. Drugs R D 2019; 19:201-212. [PMID: 31073875 PMCID: PMC6544741 DOI: 10.1007/s40268-019-0271-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Background and Objective Given that a high intrapatient variability (IPV) of tacrolimus whole blood concentration increases the risk for a poor kidney transplant outcome, some experts advocate routine IPV monitoring for detection of high-risk patients. However, attempts to estimate the variance of tacrolimus trough concentrations (TTC) are limited by the need for patients to receive a fixed dose over time and/or the use of linear statistical models. A goal of this study is to overcome the current limitations through the novel application of statistical methodology generalizing the relationship between TTC and dose through the use of nonparametric functional regression modeling. Methods With TTC as a response and dose as a covariate, the model employs an unknown bivariate function, allowing for the potentially complex, nonlinear relationship between the two parameters. A dose-adjusted variance of TTC is then derived based on standard functional principal component analysis (FPCA). To assess the model, it was compared against an FPCA-based model and linear mixed-effects models using prediction error, bias, and coverage probabilities for simulated data as well as phase III data from the Astellas new drug application studies for extended-release tacrolimus. Results Our numerical investigation indicates that the new model better predicts dose-adjusted TTCs compared with the prediction of linear mixed effects models. Estimated coverage probabilities also indicate that the new model accurately accounts for the variance of TTC during the periods of large fluctuation in dose, whereas the linear mixed effects model consistently underestimates the coverage probabilities because of the inaccurate characterization of TTC fluctuation. Conclusion This is the first known application of a functional regression model to assess complex relationships between TTC and dose in a real clinical setting. This new method has applicability in future clinical trials including real-world data sets due to flexibility of the nonparametric modeling approach. Electronic supplementary material The online version of this article (10.1007/s40268-019-0271-2) contains supplementary material, which is available to authorized users.
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Arreola-Guerra JM, Alberú J, Chew-Wong A, Macias DM, Hernández-Rosales J, Zuñiga-Macías L, Delgadillo-Castañeda R, Ricalde-Ríos G, Haro-Alcalde F, Villafán-Bernal JR, Ramos-Medellín CL, Reyes-Acevedo R. Changes in the commercial brand of tacrolimus lead to subtherapeutic trough levels and acute rejection in renal transplant recipients. Clin Transplant 2019; 33:e13749. [PMID: 31691354 DOI: 10.1111/ctr.13749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2019] [Revised: 09/28/2019] [Accepted: 10/17/2019] [Indexed: 10/25/2022]
Abstract
BACKGROUND The vigilance of tacrolimus (TAC) trough levels is an essential part of renal transplant follow up. Reduced TAC trough levels and high variability are related to adverse outcomes. The aim of this study was to evaluate the impact of brand changes on tacrolimus (TAC) subtherapeutic (SubT) trough levels, acute rejection (AR), and kidney function. METHODS This is a prospective, observational cohort study of renal transplant recipients, between January 2016 and October 2018. Tacrolimus trough levels and brand used by the patient were both registered at every consult. Tacrolimus values ≤3.5 ng/mL were considered SubT. RESULTS 445 patients were included. The median number of TAC brand changes was 2 (IQR, 1-4). Patients were grouped according to the number of brand changes: Group 1 = 0 (n = 107), Group 2 = 1-4 (n = 236), and Group 3 = ≥5 (n = 102). Patients with the greatest number of brand changes had a greater proportion and number of SubT TAC trough levels (Group 1 = 36.4%, average 0.53; Group 2 = 39.8%, average 0.65, Group 3 = 59.8%, average 1.17, P < .001) and AR (Group 1 = 0.9%, Group 2 = 11%, Group 3 = 14.7%, P < .001). On multivariate analysis, SubT levels and the number of brand changes were related to AR. CONCLUSIONS In Mexico, changes in TAC brand are associated with an elevated frequency of SubT levels. Brand changes and SubT levels are independently associated with acute rejection. The supply policies on TAC brands in Mexico require revision to avoid changing brands as much as possible.
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Affiliation(s)
- José Manuel Arreola-Guerra
- Department of Nephrology, Centenario Hospital Miguel Hidalgo, Aguascalientes, Mexico.,Department of Internal Medicine, Centenario Hospital Miguel Hidalgo, Aguascalientes, Mexico
| | - Josefina Alberú
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Mexico
| | - Alfredo Chew-Wong
- Department of Nephrology, Centenario Hospital Miguel Hidalgo, Aguascalientes, Mexico
| | - Dulce Maria Macias
- Department of Transplantation, Centenario Hospital Miguel Hidalgo, Aguascalientes, Mexico
| | - Jesus Hernández-Rosales
- Department of Histocompatibility, Laboratorios Clínicos del Campestre, Aguascalientes, Mexico
| | - Leslie Zuñiga-Macías
- Department of Nephrology, Centenario Hospital Miguel Hidalgo, Aguascalientes, Mexico
| | | | | | - Fabian Haro-Alcalde
- Department of Internal Medicine, Centenario Hospital Miguel Hidalgo, Aguascalientes, Mexico
| | | | | | - Rafael Reyes-Acevedo
- Department of Transplantation, Centenario Hospital Miguel Hidalgo, Aguascalientes, Mexico
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Triplett KN, El-Behadli AF, Masood SS, Sullivan S, Desai DM. Digital medicine program with pediatric solid organ transplant patients: Perceived benefits and challenges. Pediatr Transplant 2019; 23:e13555. [PMID: 31328842 DOI: 10.1111/petr.13555] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Revised: 05/06/2019] [Accepted: 06/18/2019] [Indexed: 11/28/2022]
Abstract
Given the complexity of the pediatric post-transplant medication regimen and known medication adherence difficulties within the solid organ transplant population, interventions to improve adherence continue to be explored and fine-tuned. Advances in technology have led to the development of new programs aimed at improving medication adherence and the overall care of transplant patients. This manuscript describes implementation of a DMP where transplant patients' medications were co-encapsulated with ingestible sensors, and adherence was monitored via a patient mobile application and a provider portal. The benefits and challenges of the DMP as reported by patients, caregivers, and medical providers are explored in this manuscript. Participant feedback regarding best practices highlighted these benefits: ease of use/intuitive technology, sense of improved communication with medical team, increased knowledge and motivation around treatment regimen, and positive self-reports of medication adherence. Challenges included reluctance to participate (n = 43, 54.43% of patients approached declined participation) and patch wearability difficulties reported by participants (n = 20; 68.97%). Other notable challenges included the following: limited drug profile compatibility with the DMP technology and concerns about privacy and electronic data sharing for patients who chose not to participate. DMP implementation highlighted how technological advances offer novel methods to assess adherence, enhance medical decision-making, and can potentially improve clinical outcomes. Although numerous benefits of the program were recognized by participants, challenges were identified and the DMP technology and medication panel continues to be refined; further investigation of such programs continues to be warranted.
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Affiliation(s)
- Kelli N Triplett
- Solid Organ Transplant Department, Children's Health - Children's Medical Center, Dallas, Texas.,University of Texas Southwestern Medical Center, Dallas, Texas
| | - Ana F El-Behadli
- Solid Organ Transplant Department, Children's Health - Children's Medical Center, Dallas, Texas.,University of Texas Southwestern Medical Center, Dallas, Texas
| | - Saba S Masood
- Solid Organ Transplant Department, Children's Health - Children's Medical Center, Dallas, Texas.,University of Texas Southwestern Medical Center, Dallas, Texas
| | - Sarah Sullivan
- Solid Organ Transplant Department, Children's Health - Children's Medical Center, Dallas, Texas
| | - Dev M Desai
- Solid Organ Transplant Department, Children's Health - Children's Medical Center, Dallas, Texas.,University of Texas Southwestern Medical Center, Dallas, Texas
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Fernandez HE, Amaral S, Shaw PA, Doyle AM, Bloom RD, Palmer JA, Baluarte HJ, Furth SL. The effect of transfer to adult transplant care on kidney function and immunosuppressant drug level variability in pediatric kidney transplant recipients. Pediatr Transplant 2019; 23:e13527. [PMID: 31209988 DOI: 10.1111/petr.13527] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Revised: 03/30/2019] [Accepted: 05/12/2019] [Indexed: 11/29/2022]
Abstract
Adolescent age at time of transplant has been recognized as a risk factor for renal allograft loss. Increased risk for graft failure may persist from adolescence to young adulthood. Transfer of care is hypothesized as a risk factor for non-adherence and graft loss. We explored whether kidney allograft function declined at an accelerated rate after transfer of care to adult transplant centers and whether coefficient of variation of tacrolimus (CV TAC) trough levels predicted allograft loss. Single-center, retrospective chart review was performed for pediatric kidney transplant recipients who received transplants between 1999 and 2011. Change in eGFR pre- and post-transfer was performed via a linear mixed-effects model. CV TAC was calculated in transplant recipients with TAC data pre- and post-transfer. t test was performed to determine the difference between means of CV TAC in subjects with and without allograft loss following transfer of care. Of the 138 subjects who transferred to adult care, 47 subjects with data pre- and post-transfer demonstrated a decrease in the rate of eGFR decline post-transfer from 8.0 mL/min/1.73 m2 per year to 2.1 mL/min/1.73 m2 per year, an ~80% decrease in eGFR decline post-transfer (P = 0.01). Twenty-four subjects had CV TAC data pre- and post-transfer of care. Pretransfer CV TAC for subjects with allograft loss post-transfer was significantly higher than in subjects without allograft loss (49% vs 26%, P < 0.05). Transfer of care was not independently associated with acceleration in eGFR decline. CV TAC may aid in identifying patients at risk for allograft loss post-transfer.
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Affiliation(s)
- Hilda E Fernandez
- Division of Nephrology, Department of Medicine, Columbia University Medical Center, New York, New York
| | - Sandra Amaral
- Division of Nephrology, Department of Pediatrics, Children's Hospital of Philadelphia, and University of Pennsylvania, Philadelphia, Pennsylvania.,Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Pamela A Shaw
- Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Alden M Doyle
- Division of Nephrology, University of Virginia School of Medicine, Charlottesville, Virginia
| | - Roy D Bloom
- Renal Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Jo Ann Palmer
- Division of Nephrology, Department of Pediatrics, Children's Hospital of Philadelphia, and University of Pennsylvania, Philadelphia, Pennsylvania
| | - Hobart J Baluarte
- Division of Nephrology, Department of Pediatrics, Children's Hospital of Philadelphia, and University of Pennsylvania, Philadelphia, Pennsylvania
| | - Susan L Furth
- Division of Nephrology, Department of Pediatrics, Children's Hospital of Philadelphia, and University of Pennsylvania, Philadelphia, Pennsylvania.,Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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Association of Intrapatient Variability of Tacrolimus Concentration With Early Deterioration of Chronic Histologic Lesions in Kidney Transplantation. Transplant Direct 2019; 5:e455. [PMID: 31321291 PMCID: PMC6553623 DOI: 10.1097/txd.0000000000000899] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Revised: 04/04/2019] [Accepted: 04/06/2019] [Indexed: 12/22/2022] Open
Abstract
Supplemental Digital Content is available in the text. High intrapatient variability (IPV) of tacrolimus (Tac) is increasingly recognized as a risk factor for poor graft outcomes in kidney transplantation. The timing of onset of its impact on kidney histologic lesions has not been investigated.
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Adherence Behavior in Subjects on Hemodialysis Is Not a Clear Predictor of Posttransplantation Adherence. Kidney Int Rep 2019; 4:1122-1130. [PMID: 31440702 PMCID: PMC6698287 DOI: 10.1016/j.ekir.2019.04.028] [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: 10/18/2018] [Revised: 03/15/2019] [Accepted: 04/29/2019] [Indexed: 12/05/2022] Open
Abstract
Introduction Nonadherence is common in both hemodialysis (HD) and kidney transplant recipients and is a major risk factor for poor clinical outcomes. This retrospective study explored whether nonadherent HD patients become nonadherent transplant recipients. Methods Data were collected for 88 patients from the electronic patient system at a subregional renal unit about adherence to HD regimens in the 6 months before transplantation, and for 1 year posttransplantation following return transfer to the posttransplantation clinic from the transplanting center. Pretransplantation definitions of nonadherence included whether the patients: on average, shortened their dialysis prescription by >10 minutes; shortened it by >15 minutes; missed 2 or more HD sessions; and had mean serum phosphate levels >1.8mmol/l. Posttransplantation definitions of nonadherence included mean tacrolimus levels outside 5 to 10 ng/ml; and missed 1 or more posttransplantation clinic appointments. Results Nonadherence ranged from 25% to 42% pretransplantation and from 15.9% to 22.7% posttransplantation, depending on how it was operationalized. There was little relationship between pretransplantation data and posttransplantation adherence, with the exception of a significant relationship between pretransplantation phosphate and posttransplantation clinic attendance. Patients who had missed 1 or more transplant clinic appointments had higher mean pretransplantation phosphate levels. Nonadherent patients with high phosphate levels pretransplantation and missed clinic appointments posttransplantation were significantly younger. Conclusion Our findings provide little support for the likelihood of a strong direct relationship between pre and posttransplantation behaviors. The findings require confirmation and further research to assess whether interventions in relation to pretransplantation adherence may enhance adherence posttransplantation and improve outcomes.
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Almardini R, Taybeh EO, Alsous MM, Hawwa AF, McKeever K, Horne R, McElnay JC. A multiple methods approach to determine adherence with prescribed mycophenolate in children with kidney transplant. Br J Clin Pharmacol 2019; 85:1434-1442. [PMID: 30845359 DOI: 10.1111/bcp.13911] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2017] [Revised: 02/07/2019] [Accepted: 02/09/2019] [Indexed: 12/22/2022] Open
Abstract
AIMS The aim of this study was, to use a multiple methods approach, including, for the first time, dried blood spot (DBS) sampling with population pharmacokinetic interpretation, to assess adherence to mycophenolate in children with kidney transplant. A second aim was to identify patient/parental factors that influenced adherence and to link adherence behaviour to clinical outcomes. METHODS A convenience sample of 33 children with kidney transplant (age ≤ 18 years) who had been prescribed mycophenolate for at least 3 months were recruited from participating outpatient clinics in the UK and Jordan. Medication adherence was determined via self-report questionnaires, medication refill data from dispensing records, and via mycophenolic acid concentrations in plasma and DBS samples obtained from children during a clinic visit. RESULTS Through triangulation of results from the different methodological approaches a total of 12 children (36.4%) were deemed to be nonadherent with their prescribed mycophenolate treatment. Logistic regression analysis indicated that nonadherence was significantly associated with the presence of mycophenolate side effects. Poor adherence was positively linked to measures of poor clinical outcomes (hospitalisation and the need for kidney biopsy). CONCLUSIONS Despite the imperative regarding medication adherence to help prevent organ rejection, a significant proportion of children are not fully adherent with their therapy. Side-effects appear to be an important factor leading to nonadherence. Measurement of mycophenolate in DBS samples, coupled with the use of population pharmacokinetics modelling, was a convenient direct approach to assessing adherence in children with kidney transplant and has the potential to be introduced into routine practice.
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Affiliation(s)
- Reham Almardini
- Department of Pediatric Nephrology, King Hussien Medical Center, Amman, Jordan
| | - Esra' O Taybeh
- Department of Applied Pharmaceutical Sciences, School of Pharmacy, Isra University, Amman, Jordan.,Clinical and Practice Research Group, School of Pharmacy, Queen's University Belfast, Belfast, UK
| | - Mervat M Alsous
- Department of Pharmacy Practice, School of Pharmacy, Yarmouk University, Irbid, Jordan
| | - Ahmed F Hawwa
- Clinical and Practice Research Group, School of Pharmacy, Queen's University Belfast, Belfast, UK
| | - Karl McKeever
- Department of Paediatric Nephrology, Royal Belfast Hospital for Sick Children, Belfast, UK
| | - Rob Horne
- Centre for Behavioural Medicine, UCL School of Pharmacy, University College London, London, UK
| | - James C McElnay
- Clinical and Practice Research Group, School of Pharmacy, Queen's University Belfast, Belfast, UK
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Defrancq C, De Wilde N, Raes A, Van Biervliet S, Vande Velde S, Van Winckel M, De Bruyne R, Prytuła A. Intra-patient variability in tacrolimus exposure in pediatric liver transplant recipients: Evolution, risk factors, and impact on patient outcomes. Pediatr Transplant 2019; 23:e13388. [PMID: 30916883 DOI: 10.1111/petr.13388] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2018] [Revised: 01/09/2019] [Accepted: 02/14/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND This study aims to investigate the evolution and factors associated with TAC IPV and its impact on patient outcomes in pediatric LT recipients. METHODS This is a retrospective study including 41 children. The TAC IPV was expressed as the coefficient of variation and was calculated for years 1-5 following LT. The number of missed clinic appointments was used as a surrogate marker for therapy adherence. RESULTS We identified a decrease in the TAC IPV during the first 3 years after LT (P < 0.01). Serum albumin in the first year (P = 0.03), hematocrit (P = 0.02) and total bilirubin (P = 0.04) in the third year, and therapy adherence (P < 0.01) in the fifth year were associated with TAC IPV. High TAC IPV was associated with biopsy-proven acute allograft rejection (P = 0.04) and the need for biopsy during the first year (P = 0.02). There was a borderline association between TAC IPV and donor-specific antibodies (P = 0.08) and CMV viremia (P = 0.07). High TAC IPV was a predictor of need for liver biopsy and AR with an odds ratio of 1.04 (95% CI 1.0-1.1; P = 0.03) and 1.04 (95% CI 1.0-1.1; P = 0.05), respectively. CONCLUSIONS Our results highlight the impact of biological factors on TAC IPV during the early LT follow-up and later also therapy adherence. High TAC IPV may be associated with adverse patient outcomes.
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Affiliation(s)
- Charlotte Defrancq
- Department of Pediatric Nephrology and Rheumatology, Ghent University Hospital, Ghent, Belgium
| | - Nika De Wilde
- Department of Pediatric Nephrology and Rheumatology, Ghent University Hospital, Ghent, Belgium
| | - Ann Raes
- Department of Pediatric Nephrology and Rheumatology, Ghent University Hospital, Ghent, Belgium.,Safepedrug Consortium
| | - Stephanie Van Biervliet
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Ghent University Hospital, Ghent, Belgium
| | - Saskia Vande Velde
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Ghent University Hospital, Ghent, Belgium
| | - Myriam Van Winckel
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Ghent University Hospital, Ghent, Belgium
| | - Ruth De Bruyne
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Ghent University Hospital, Ghent, Belgium
| | - Agnieszka Prytuła
- Department of Pediatric Nephrology and Rheumatology, Ghent University Hospital, Ghent, Belgium
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Mansell H, Rosaasen N, West-Thielke P, Wichart J, Daley C, Mainra R, Shoker A, Liu J, Blackburn D. Randomised controlled trial of a video intervention and behaviour contract to improve medication adherence after renal transplantation: the VECTOR study protocol. BMJ Open 2019; 9:e025495. [PMID: 30872550 PMCID: PMC6429879 DOI: 10.1136/bmjopen-2018-025495] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
INTRODUCTION Non-adherence after kidney transplantation contributes to increased rejections, hospitalisations and healthcare expenditures. Although effective adherence interventions are sorely needed, increasing education and support to transplant recipients demands greater use of care providers' time and resources in a healthcare system that is stretched. The objective of this clinical trial is to determine the effectiveness of an electronically delivered video series and adherence behaviour contract on improving medication adherence to immunosuppressant medications. METHODS AND ANALYSIS A multicentre, parallel arm, randomised controlled trial will be conducted with four sites across North America (Saskatoon, Calgary, Halifax, Chicago). Adult patients will be randomised (1:1) to either the intervention (ie, home-based video education +behaviour contract plus usual care) or usual care alone. De novo transplant recipients will be enrolled prior to their hospital discharge and will be provided with electronic access to the video intervention (immediately) and adherence contract (1 month post-transplant). Follow-up electronic surveys will be provided at 3 and 12 months postenrolment. The primary outcome will be adherence at 12 months post-transplant, as measured by self-report Basel Assessment of Adherence to Immunosuppressive medications and immunosuppressant levels. Secondary outcomes include the difference in knowledge score between the intervention and control in groups (measured by the Kidney Transplant Understanding Tool); differences in self-efficacy (Generalised Self-efficacy Scale), Beliefs of Medicine Questionnaire (BMQ), quality of life (Short Form-12), patient satisfaction and cost utilisation. The study aims to recruit at least 200 participants across participating sites. ETHICS AND DISSEMINATION Ethical approval was obtained from the University of Saskatchewan Behavioural Ethics Committee (Beh 18-63), and all patients provide informed consent prior to participating. This educational intervention aims to improve information retention and self-efficacy, leading to improved medication adherence after kidney transplantation, at low cost, with little impact to existing healthcare personnel. If proven beneficial, delivery can be easily implemented into standard of care. TRIAL REGISTRATION NUMBER NCT03540121; Pre-results.
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Affiliation(s)
- Holly Mansell
- College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Nicola Rosaasen
- Saskatchewan Transplant Program, Saskatchewan Health Authority, Saskatoon, Saskatchewan, Canada
| | - Patricia West-Thielke
- Department of Surgery, University of Illinois Hospital and Health Sciences System, Chicago, Illinois, USA
| | - Jenny Wichart
- Southern Alberta Transplant Program, Alberta Health Services, Calgary, Alberta, Canada
| | - Christopher Daley
- Multi-organ Transplant Program of Atlantic Canada, Halifax, Nova Scotia, Canada
| | - Rahul Mainra
- College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Ahmed Shoker
- College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Juxin Liu
- College of Arts and Science, University of Saskatchewan, Saskatoon, SK, Canada
| | - David Blackburn
- College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
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Gustavsen MT, Midtvedt K, Lønning K, Jacobsen T, Reisaeter AV, De Geest S, Andersen MH, Hartmann A, Åsberg A. Evaluation of tools for annual capture of adherence to immunosuppressive medications after renal transplantation - a single-centre open prospective trial. Transpl Int 2019; 32:614-625. [DOI: 10.1111/tri.13412] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2018] [Revised: 10/19/2018] [Accepted: 02/11/2019] [Indexed: 01/15/2023]
Affiliation(s)
- Marte Theie Gustavsen
- Department of Transplantation Medicine; Oslo University Hospital, Rikshospitalet; Oslo Norway
- School of Pharmacy; University of Oslo; Oslo Norway
| | - Karsten Midtvedt
- Department of Transplantation Medicine; Oslo University Hospital, Rikshospitalet; Oslo Norway
| | - Kjersti Lønning
- Department of Transplantation Medicine; Oslo University Hospital, Rikshospitalet; Oslo Norway
- Faculty of Medicine; Institute of Clinical Medicine; University of Oslo; Oslo Norway
| | | | - Anna Varberg Reisaeter
- Department of Transplantation Medicine; Oslo University Hospital, Rikshospitalet; Oslo Norway
- Norwegian Renal Registry; Oslo University Hospital, Rikshospitalet; Oslo Norway
| | - Sabina De Geest
- Institute of Nursing Science; University of Basel; Basel Switzerland
- Academic Centre for Nursing and Midwifery; KU-Leuven; Leuven Belgium
| | - Marit Helen Andersen
- Department of Transplantation Medicine; Oslo University Hospital, Rikshospitalet; Oslo Norway
- Department of Health Sciences; Faculty of Medicine; University of Oslo; Oslo Norway
| | - Anders Hartmann
- Department of Transplantation Medicine; Oslo University Hospital, Rikshospitalet; Oslo Norway
- Faculty of Medicine; Institute of Clinical Medicine; University of Oslo; Oslo Norway
| | - Anders Åsberg
- Department of Transplantation Medicine; Oslo University Hospital, Rikshospitalet; Oslo Norway
- School of Pharmacy; University of Oslo; Oslo Norway
- Norwegian Renal Registry; Oslo University Hospital, Rikshospitalet; Oslo Norway
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High Calcineurin Inhibitor Intrapatient Variability Is Associated With Renal Allograft Inflammation, Chronicity, and Graft Loss. Transplant Direct 2019; 5:e424. [PMID: 30882028 PMCID: PMC6415973 DOI: 10.1097/txd.0000000000000862] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Accepted: 12/26/2018] [Indexed: 12/21/2022] Open
Abstract
Background High calcineurin inhibitor (CNI) intrapatient variability (IPV) has been associated with poor kidney allograft outcomes. However, the relationship between early allograft histological changes, their progression, and CNI-IPV is less well studied. Hence, we evaluated effect of CNI-IPV defined by the degree of fluctuation of CNI levels in all kidney transplant patients over 2 to 12 months posttransplant on early allograft inflammation, subsequent chronicity, and later clinical outcomes. Methods Two hundred eighty-six patients transplanted from January 2013 to November 2014 were enrolled with protocol and indication biopsies. The mean CNI-IPV was 28.5% and a quarter of our cohort had IPV of 35% or greater (high CNI IPV). Baseline demographic differences were similar between high and low CNI IPV groups. Results High CNI-IPV was associated with a higher incidence of acute rejection (AR) within 1 year (52% vs 31% P < 0.001), more persistent/recurrent AR by 1 year (18.2% vs 6.2%, P = 0.002), higher-grade AR (≥Banff 1B, 27.5% vs 7.3%, P < 0.001), and worse interstitial fibrosis/tubular atrophy (P = 0.005). High CNI-IPV was associated with increased graft loss (GL) and impending graft loss (iGL, defined as eGFR<30 ml/min and >30% decline in eGFR from baseline), regardless of donor-specific antibody, delayed graft function, rejection, or race. In a multivariate Cox Proportional Hazards Model, high CNI-IPV was independently associated with GL + iGL (hazard ratio, 3.1; 95% confidence interval, 1.6-5.9, P < 0.001). Conclusions High CNI-IPV within 1 year posttransplant is associated with higher incidence of AR, severe AR, allograft chronicity, GL, and iGL. This represents a subset of patients who are at risk for poor kidney transplant outcomes and potentially a modifiable risk factor for late allograft loss.
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Seibert SR, Schladt DP, Wu B, Guan W, Dorr C, Remmel RP, Matas AJ, Mannon RB, Israni AK, Oetting WS, Jacobson PA. Tacrolimus trough and dose intra-patient variability and CYP3A5 genotype: Effects on acute rejection and graft failure in European American and African American kidney transplant recipients. Clin Transplant 2018; 32:e13424. [PMID: 30318646 PMCID: PMC6317347 DOI: 10.1111/ctr.13424] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Revised: 09/18/2018] [Accepted: 10/08/2018] [Indexed: 02/01/2023]
Abstract
BACKGROUND Suboptimal immunosuppression after kidney transplantation contributes to toxicity and loss of efficacy. Little is known regarding the impact of intra-patient variability of tacrolimus (TAC) doses and troughs in the early post-transplant period or the influence of genetic variants on variability. METHODS Coefficients of variation (CV) of TAC troughs and doses of 1226 European American (EA) and 246 African American (AA) adult recipients enrolled in DeKAF Genomics were compared for association with acute rejection and graft failure. Additionally, the influence of recipients' number of CYP3A5 loss-of-function alleles was assessed. RESULTS Acute rejection was associated with greater CV of dose in AA (P < 0.001) and EA recipients (P = 0.012). Graft failure was associated with a greater CV of dose (P = 0.022) and trough (P < 0.001) in AA, and higher CV of trough (P = 0.024) in EA recipients. In EA, CYP3A5 loss-of-function alleles were associated with decreased CV of trough (P = 0.0042) and increased CV of dose (P < 0.0001). CONCLUSION CYP3A5 loss-of-function alleles influence intra-patient TAC trough and dose variability. High variability of TAC dose increases risk of acute rejection. High variability of TAC trough increases risk of graft failure. Early clinical recognition of TAC dose and trough variability may improve patient management and outcomes.
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Affiliation(s)
- Stephan R Seibert
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota
| | - David P Schladt
- Chronic Disease Research Group, Minneapolis Medical Research Foundation, Hennepin County Medical Center, Minneapolis, Minnesota
| | - Baolin Wu
- Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota
| | - Weihua Guan
- Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota
| | - Casey Dorr
- Minneapolis Medical Research Foundation, Hennepin County Medical Center, Minneapolis, Minnesota
| | - Rory P Remmel
- Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota
| | - Arthur J Matas
- Department of Surgery, University of Minnesota, Minneapolis, Minnesota
| | - Roslyn B Mannon
- Department of Nephrology, University of Alabama, Birmingham, Alabama
| | - Ajay K Israni
- Division of Nephrology, Hennepin County Medical Center, Epidemiology & Community Health, University of Minnesota, Minneapolis, Minnesota
| | - William S Oetting
- Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota
| | - Pamala A Jacobson
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota
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Gueta I, Markovits N, Yarden-Bilavsky H, Raichlin E, Freimark D, Lavee J, Loebstein R, Peled Y. High tacrolimus trough level variability is associated with rejections after heart transplant. Am J Transplant 2018; 18:2571-2578. [PMID: 29989311 DOI: 10.1111/ajt.15016] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Revised: 06/11/2018] [Accepted: 07/01/2018] [Indexed: 01/25/2023]
Abstract
Tacrolimus, the major immunosuppressant after heart transplant (HTx) therapy, is a narrow therapeutic index drug. Hence, achieving stable therapeutic steady state plasma concentrations is essential to ensure efficacy while avoiding toxicity. Whether high variability in steady state concentrations is associated with poor outcomes is unknown. We investigated the association between tacrolimus trough level variability during the first year post-HTx and outcomes during and beyond the first postoperative year. Overall, 72 patients were analyzed for mortality, of whom 65 and 61 were available for rejection analysis during and beyond the first year post-HTx, respectively. Patients were divided into high (median >28.8%) and low tacrolimus level variability (<28.8%) groups. Mean tacrolimus levels did not differ between the groups (12.7 ± 3.4 ng/mL vs 12.8 ± 2.4 ng/mL, P = .930). Patients in the high variability group exhibited higher long-term rejection rate (median total rejection score: 0.33 vs 0, P = .04) with no difference in rejection scores within the first year post-HTx. Multivariate analysis showed that high tacrolimus trough level variability was associated with >8-fold increased risk for any rejection beyond the first year post-HTx (P = .011). Mortality was associated only with cardiovascular complications (P = .018), with no effect of tacrolimus through level variability.
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Affiliation(s)
- Itai Gueta
- The Institute of Clinical Pharmacology, Sheba Medical Center, Tel Hashomer, Israel.,Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Noa Markovits
- The Institute of Clinical Pharmacology, Sheba Medical Center, Tel Hashomer, Israel.,Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Havatzelet Yarden-Bilavsky
- The Institute of Clinical Pharmacology, Sheba Medical Center, Tel Hashomer, Israel.,Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Eugenia Raichlin
- Division of Cardiology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Dov Freimark
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.,The Olga and Lev Leviev Heart Center, Sheba Medical Center, Ramat Gan, Israel
| | - Jacob Lavee
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.,The Olga and Lev Leviev Heart Center, Sheba Medical Center, Ramat Gan, Israel
| | - Ronen Loebstein
- The Institute of Clinical Pharmacology, Sheba Medical Center, Tel Hashomer, Israel.,Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Yael Peled
- Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.,The Olga and Lev Leviev Heart Center, Sheba Medical Center, Ramat Gan, Israel
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