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Killian MO, Little C, Mayewski SE. Changes in Medication Adherence Across the Posttransplant Period in Pediatric Organ Transplant Recipients. Clin Transplant 2024; 38:e15442. [PMID: 39385672 PMCID: PMC11469551 DOI: 10.1111/ctr.15442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 06/14/2024] [Accepted: 08/15/2024] [Indexed: 10/12/2024]
Abstract
INTRODUCTION Limited research has explored immunosuppressant medication adherence over time in pediatric transplant patients, who often struggle with posttransplant regimen adherence, resulting in poor outcomes. METHODS This study investigated the longitudinal growth in immunosuppressive medication levels following transplantation. Medication level variability index (MLVI) scores from tacrolimus blood levels of pediatric organ transplant recipients at a major medical center were analyzed. Linear mixed effect models (LMEM) assessed individual MLVI change trajectories and predictors of growth, exploring both linear and curvilinear growth patterns posttransplant. RESULTS A sample of 181 patients with at least 4 years of MLVI data were analyzed. Growth curve modeling identified the cubic model as the best fit for the quarterly MLVI values, which significantly decreased within the first 2 years posttransplant before stabilizing. Gender significantly predicted MLVI change, with females showing greater MLVI decreases, while age at transplant did not significantly predict changes. Significant variation in MLVI among individual patients was found in all models. CONCLUSIONS The study demonstrated a significant decrease in MLVI values over time, indicating improved medication adherence in pediatric transplant patients, with females exhibiting more adherent growth patterns than males. Future research should aim to identify pediatric patients at high risk of nonadherence.
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Affiliation(s)
- Michael O. Killian
- College of Social Work, Florida State University
- College of Medicine, Florida State University
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Lattimore S, Chambers A, Angeli-Pahim I, Shrestha A, Eke BO, Pomputius A, Bylund C, Gregory ME, Zarrinpar A. Impact of Intrapatient Immunosuppression Variability in Liver Transplantation Outcomes: A Systematic Review and Meta-analysis. Transplant Direct 2024; 10:e1700. [PMID: 39188531 PMCID: PMC11346865 DOI: 10.1097/txd.0000000000001700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 07/09/2024] [Accepted: 07/11/2024] [Indexed: 08/28/2024] Open
Abstract
Background To investigate the impact of intrapatient variability (IPV) in the levels of immunosuppressant drugs on health outcomes after liver transplantation. Methods A comprehensive systematic review and meta-analysis were conducted, examining literature from MEDLINE/PubMed, Embase, Web of Science, Cochrane Reviews, and Cochrane CENTRAL. Results The analysis focused on acute rejection, graft survival, acute kidney injury, and cancer risk as health outcomes. Of 2901 articles screened, 10 met the inclusion criteria. The results indicate a 19% reduction in the risk of acute rejection in patients with lower IPV (RR = 0.81; 95% confidence interval, 0.66-0.99), although 6 studies found no significant association between high IPV and acute rejection. Contrasting results were observed for graft survival, with 1 study indicating worse outcomes for high IPV, whereas another reported no significant difference. High IPV was consistently associated with acute kidney injury across 3 studies. One study suggested a link between high IPV and hepatocellular carcinoma, although a meta-analysis for these outcomes was not feasible. Conclusions These findings point to a marginal but statistically significant association between high IPV and an increased risk of acute rejection, highlighting the importance of precise management of immunosuppressive drugs in liver transplant recipients to enhance patient outcomes.
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Affiliation(s)
| | | | | | | | - Benjamin O. Eke
- Department of Surgery, University of Florida, Gainesville, FL
| | - Ariel Pomputius
- Health Sciences Library, University of Florida, Gainesville, FL
| | - Carma Bylund
- Department of Health Outcomes and Biomedical Science, University of Florida, Gainesville, FL
| | - Megan E. Gregory
- Department of Health Outcomes and Biomedical Science, University of Florida, Gainesville, FL
| | - Ali Zarrinpar
- Division of Transplantation and Hepatobiliary Surgery, University of Florida, Gainesville, FL
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Soares ME, Costa G, Guerra L, Morais MC, Vaz N, Codes L, Bittencourt PL. Influence of Tacrolimus Intrapatient Variability on Allograft Rejection Frequency and Survival Following Liver Transplantation. Ther Drug Monit 2024; 46:456-459. [PMID: 38648652 DOI: 10.1097/ftd.0000000000001192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Accepted: 01/26/2024] [Indexed: 04/25/2024]
Abstract
BACKGROUND Tacrolimus is the primary calcineurin inhibitor used in immunosuppressive regimens to prevent allograft rejection (AR) after organ transplantation. Recent studies have linked intrapatient variability (IPV) of tacrolimus with AR occurrence and reduced survival, especially in kidney transplant recipients. However, limited data are available on the impact of tacrolimus IPV on adverse outcomes after liver transplantation (LT). AIMS The aim of this study was to assess the association between tacrolimus IPV using various methodologies with acute AR and long-term patient survival after LT. METHODS All patients who underwent LT from January 2010 to July 2021 were retrospectively evaluated. Tacrolimus IPV was calculated for each patient using the mean and SD, mean absolute deviation (MAD), coefficient of variation (CV), and time in therapeutic range (TTR). These measures were then compared with AR within the first 24 months after LT and to long-term survival. RESULTS Out of 234 patients, 32 (13.7%) developed AR and 183 (78.2%) survived, with a mean follow-up of 101 ± 43 months. Tacrolimus IPV, assessed by mean, SD, MAD, and CV, was 8.3 ± 2.1, 2.7 ± 1.3, 32.0% ± 11.7%, and 39.4% ± 15.4%, respectively. There was no statistically significant correlation between Tacrolimus IPV and AR or survival post-LT. CONCLUSIONS In a large cohort of patients from diverse racial backgrounds, tacrolimus IPV was not associated with clinically relevant outcomes such as AR and survival after LT.
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Affiliation(s)
| | - Gabriela Costa
- Bahiana School of Medicine and Public Health, Salvador, Bahia, Brazil ; and
| | - Laura Guerra
- Bahiana School of Medicine and Public Health, Salvador, Bahia, Brazil ; and
| | - Maria Clara Morais
- Bahiana School of Medicine and Public Health, Salvador, Bahia, Brazil ; and
| | - Nayana Vaz
- Unit of Gastroenterology and Hepatology, Portuguese Hospital, Salvador, Bahia, Brazil
| | - Liana Codes
- Bahiana School of Medicine and Public Health, Salvador, Bahia, Brazil ; and
- Unit of Gastroenterology and Hepatology, Portuguese Hospital, Salvador, Bahia, Brazil
| | - Paulo Lisboa Bittencourt
- Bahiana School of Medicine and Public Health, Salvador, Bahia, Brazil ; and
- Unit of Gastroenterology and Hepatology, Portuguese Hospital, Salvador, Bahia, Brazil
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Zanatta E, Patron E, Messerotti Benvenuti S, Pelizzaro F, Russo FP, Gambato M, Germani G, Ferrarese A, Zanetto A, Battermann F, Buccheri F, Cavalli C, Schiavo R, Ghisi M, Pasquato S, Feltracco P, Cillo U, Burra P, Senzolo M. Alcoholic Etiology, Severity of Liver Disease, and Post-Transplant Adherence Are Correlated with Worse Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT) in Liver Transplant Candidates. J Clin Med 2024; 13:3807. [PMID: 38999373 PMCID: PMC11242210 DOI: 10.3390/jcm13133807] [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: 05/10/2024] [Revised: 06/25/2024] [Accepted: 06/26/2024] [Indexed: 07/14/2024] Open
Abstract
Introduction: Psychosocial pre-transplant evaluation in patients undergoing liver transplantation (LT) could help identify those patients at higher risk of pharmacological non-adherence, organ rejection, and mortality. The Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT) is a validated tool for assessing LT candidates' psychosocial well-being. Data on the ability of the SIPAT evaluation to predict post-transplant outcomes are sparse. Material and Methods: clinical and psychosocial data from a sample of 134 candidates for LT were analyzed. Moreover, the association between pre-transplant psychosocial evaluation and post-transplant clinical outcomes, including organ rejection, mortality, and immunosuppressant drug adherence, was calculated. Results: At the pre-transplant evaluation, patients who showed high SIPAT scores (77, 57%) also had more liver disease assessed by model for end-stage liver disease (MELD; F = 5.04; p < 0.05), alcoholic etiology (F = 35.80; p < 0.001), encephalopathy (F = 5.02; p < 0.05), and portal hypertension (F = 7.45; p < 0.01). Of the 51 transplant patients, those who had a high pre-transplant SIPAT score showed lower post-transplant immunosuppressive adherence, linked to more frequent immunological events. Conclusions: Patients with an alcoholic etiology of liver disease and more severe liver dysfunction are likelier to not adhere to medical prescriptions following transplantation. Current data suggests that this specific group of patients could benefit from early psychological pre-habilitation before undergoing liver transplantation.
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Affiliation(s)
- Elisa Zanatta
- Multivisceral Transplant Unit-Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, 35128 Padua, Italy
| | - Elisabetta Patron
- Department of General Psychology, University of Padua, 35151 Padua, Italy
| | - Simone Messerotti Benvenuti
- Department of General Psychology, University of Padua, 35151 Padua, Italy
- Hospital Psychology Unit, Padua University Hospital, 35128 Padua, Italy
- Padova Neuroscience Center (PNC), University of Padua, 35131 Padua, Italy
| | - Filippo Pelizzaro
- Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, 35128 Padua, Italy
| | - Francesco Paolo Russo
- Multivisceral Transplant Unit-Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, 35128 Padua, Italy
| | - Martina Gambato
- Multivisceral Transplant Unit-Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, 35128 Padua, Italy
| | - Giacomo Germani
- Multivisceral Transplant Unit-Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, 35128 Padua, Italy
| | - Alberto Ferrarese
- Multivisceral Transplant Unit-Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, 35128 Padua, Italy
| | - Alberto Zanetto
- Multivisceral Transplant Unit-Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, 35128 Padua, Italy
| | | | | | - Chiara Cavalli
- Hospital Psychology Unit, Padua University Hospital, 35128 Padua, Italy
| | - Rossana Schiavo
- Hospital Psychology Unit, Padua University Hospital, 35128 Padua, Italy
| | - Marta Ghisi
- Department of General Psychology, University of Padua, 35151 Padua, Italy
- Hospital Psychology Unit, Padua University Hospital, 35128 Padua, Italy
| | - Sara Pasquato
- Hospital Psychology Unit, Padua University Hospital, 35128 Padua, Italy
| | - Paolo Feltracco
- Department of Medicine, UO Anesthesia and Intensive Care, University of Padua, 35128 Padua, Italy
| | - Umberto Cillo
- Hepatobiliary Surgery and Liver Transplant Unit, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padua, Italy
| | - Patrizia Burra
- Multivisceral Transplant Unit-Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, 35128 Padua, Italy
| | - Marco Senzolo
- Multivisceral Transplant Unit-Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, 35128 Padua, Italy
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Householder S, Ramakrishnan A, Chen JK, Gorsch L, Tsapepas D, Lobritto S, Rundle A, Vittorio JM. The use of once-daily LCP-Tacrolimus with adolescent and young adult solid organ transplant recipients. Pediatr Transplant 2024; 28:e14777. [PMID: 38702932 DOI: 10.1111/petr.14777] [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: 01/16/2024] [Revised: 04/17/2024] [Accepted: 04/22/2024] [Indexed: 05/06/2024]
Abstract
BACKGROUND Adolescent and young adult (AYA) solid organ transplant (SOT) recipients experience increased rates of rejection and graft loss surrounding the time of health care transition, in part due to poor medication adherence. This study aims to examine the impact of a once-daily formulation of tacrolimus, LCP-tacrolimus (LCPT), on medication adherence for AYA SOT patients. METHODS A retrospective descriptive analysis was performed for all patients who underwent SOT and were prescribed LCPT after the age of 12 at our single-center pediatric hospital. Medication adherence was assessed via provider documentation and the medication level variability index (MLVI). RESULTS Twenty-nine patients were prescribed LCPT as part of their immunosuppression regimen. Twenty patients were converted to LCPT from immediate-acting (IR) tacrolimus; six patients were initiated immediately following transplant, and three patients were unable to receive LCPT due to insurance denial. There was a numeric improvement in medication adherence for converted patients when measured by provider assessment (45.0% vs. 68.4%, p = .140) and MLVI (40.0% vs. 71.4%, p = .276), though these did not reach statistical significance. There were no differences in episodes of rejection or adverse effects. LCPT prescription was not associated with decreased medication burden, and two patients transitioned back to IR tacrolimus due to increased cost. CONCLUSIONS LCPT use did not significantly improve patient adherence; however, it resulted in numerically higher perceived and measured adherence rates. LCPT appears to be safe and effective in the management of SOT recipients; however, it may not affect pill burden and may result in a higher financial burden. Use may be considered for a select group of AYA SOT recipients.
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Affiliation(s)
- Sarah Householder
- Vagelos College of Physicians and Surgeons, New York, New York, USA
- Department of Pediatrics, Department of Internal Medicine, Yale-New Haven Hospital, New Haven, Connecticut, USA
| | | | - Justin K Chen
- Department of Pharmacy, New York-Presbyterian Hospital, New York, New York, USA
- Department of Pharmacy, Children's Healthcare of Atlanta, Atlanta, Georgia, USA
| | - Lindsey Gorsch
- Vagelos College of Physicians and Surgeons, New York, New York, USA
| | - Demetra Tsapepas
- Department of Pharmacy, New York-Presbyterian Hospital, New York, New York, USA
| | - Steven Lobritto
- Division of Pediatric Gastroenterology and Hepatology, Department of Pediatrics, Columbia University Irving Medical Center, New York, New York, USA
| | - Anna Rundle
- Division of Pediatric Gastroenterology and Hepatology, Department of Pediatrics, Columbia University Irving Medical Center, New York, New York, USA
| | - Jennifer M Vittorio
- Division of Pediatric Gastroenterology and Hepatology, Department of Pediatrics, Columbia University Irving Medical Center, New York, New York, USA
- Division of Pediatric Gastroenterology and Hepatology, Department of Pediatrics, Hassenfeld Children's Hospital at NYU Langone, New York, New York, USA
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Joshi D, Nayagam J, Clay L, Yerlett J, Claridge L, Day J, Ferguson J, Mckie P, Vara R, Pargeter H, Lockyer R, Jones R, Heneghan M, Samyn M. UK guideline on the transition and management of childhood liver diseases in adulthood. Aliment Pharmacol Ther 2024; 59:812-842. [PMID: 38385884 DOI: 10.1111/apt.17904] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 10/15/2023] [Accepted: 02/03/2024] [Indexed: 02/23/2024]
Abstract
INTRODUCTION Improved outcomes of liver disease in childhood and young adulthood have resulted in an increasing number of young adults (YA) entering adult liver services. The adult hepatologist therefore requires a working knowledge in diseases that arise almost exclusively in children and their complications in adulthood. AIMS To provide adult hepatologists with succinct guidelines on aspects of transitional care in YA relevant to key disease aetiologies encountered in clinical practice. METHODS A systematic literature search was undertaken using the Pubmed, Medline, Web of Knowledge and Cochrane database from 1980 to 2023. MeSH search terms relating to liver diseases ('cholestatic liver diseases', 'biliary atresia', 'metabolic', 'paediatric liver diseases', 'autoimmune liver diseases'), transition to adult care ('transition services', 'young adult services') and adolescent care were used. The quality of evidence and the grading of recommendations were appraised using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. RESULTS These guidelines deal with the transition of YA and address key aetiologies for the adult hepatologist under the following headings: (1) Models and provision of care; (2) screening and management of mental health disorders; (3) aetiologies; (4) timing and role of liver transplantation; and (5) sexual health and fertility. CONCLUSIONS These are the first nationally developed guidelines on the transition and management of childhood liver diseases in adulthood. They provide a framework upon which to base clinical care, which we envisage will lead to improved outcomes for YA with chronic liver disease.
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Affiliation(s)
- Deepak Joshi
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, UK
| | - Jeremy Nayagam
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, UK
| | - Lisa Clay
- Paediatric Liver, GI and Nutrition service, King's College Hospital NHS Foundation Trust, London, UK
| | - Jenny Yerlett
- Paediatric Liver, GI and Nutrition service, King's College Hospital NHS Foundation Trust, London, UK
| | - Lee Claridge
- Leeds Liver Unit, St James's University Hospital, Leeds, UK
| | - Jemma Day
- Department of Psychology, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - James Ferguson
- National Institute for Health Research, Birmingham Biomedical Research Centre, University of Birmingham, Birmingham, UK
| | - Paul Mckie
- Department of Social Work, King's College Hospital NHS Foundation Trust, London, UK
| | - Roshni Vara
- Paediatric Liver, GI and Nutrition service, King's College Hospital NHS Foundation Trust, London, UK
- Evelina London Children's Hospital, London, UK
| | | | | | - Rebecca Jones
- Leeds Liver Unit, St James's University Hospital, Leeds, UK
| | - Michael Heneghan
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, UK
| | - Marianne Samyn
- Paediatric Liver, GI and Nutrition service, King's College Hospital NHS Foundation Trust, London, UK
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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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Killian MO, Little CW, Howry SK, Watkivs M, Triplett KN, Desai DM. Demographic Factors, Medication Adherence, and Post-transplant Health Outcomes: A Longitudinal Multilevel Modeling Approach. J Clin Psychol Med Settings 2024; 31:163-173. [PMID: 37589865 PMCID: PMC11487835 DOI: 10.1007/s10880-023-09970-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/26/2023] [Indexed: 08/18/2023]
Abstract
Few studies in pediatric solid organ transplantation have examined non-adherence to immunosuppressive medication over time and its associations with demographic factors and post-transplant outcomes including late acute rejection and hospitalizations. We examined longitudinal variation in patient Medication Level Variability Index (MLVI) adherence data from pediatric kidney, liver, and heart transplant recipients. Patient and administrative data from the United Network for Organ Sharing were linked with electronic health records and MLVI values for 332 patients. Multilevel mediation modeling indicated comparatively more variation in MLVI values between patients than within patients, longitudinally, over 10 years post transplant. MLVI values significantly predicted late acute rejection and hospitalization. MLVI partially mediated patient factors and post-transplant outcomes for patient age indicating adolescents may benefit most from intervention efforts. Results demonstrate the importance of longitudinal assessment of adherence and differences among patients. Efforts to promote medication adherence should be adapted to high-risk patients to increase likelihood of adherence.
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Affiliation(s)
- Michael O Killian
- College of Social Work, University Center, Florida State University, 296 Champions Way, Building C - Suite 2500, Tallahassee, FL, USA.
- College of Medicine, Florida State University, Tallahassee, FL, USA.
| | - Callie W Little
- College of Social Work, University Center, Florida State University, 296 Champions Way, Building C - Suite 2500, Tallahassee, FL, USA
| | - Savarra K Howry
- College of Social Work, University Center, Florida State University, 296 Champions Way, Building C - Suite 2500, Tallahassee, FL, USA
| | - Madison Watkivs
- College of Medicine, Florida State University, Tallahassee, FL, USA
| | - Kelli N Triplett
- Children's Health, Children's Medical Center of Dallas, Dallas, TX, USA
- University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Dev M Desai
- Children's Health, Children's Medical Center of Dallas, Dallas, TX, USA
- University of Texas Southwestern Medical Center, Dallas, TX, USA
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9
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Walters S, Yerkovich S, Hopkins PM, Leisfield T, Winks L, Chambers DC, Divithotawela C. Erratic tacrolimus levels at 6 to 12 months post-lung transplant predicts poor outcomes. JHLT OPEN 2024; 3:100043. [PMID: 40145121 PMCID: PMC11935420 DOI: 10.1016/j.jhlto.2023.100043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 03/28/2025]
Abstract
Background It has previously been described that erratic tacrolimus blood levels are associated with graft failure in kidney and liver transplantation. Using a small cohort, we previously described that a higher tacrolimus standard deviation (SD) 6 to 12 months after lung transplantation increased the risk of chronic lung allograft dysfunction (CLAD) and death. We aimed to assess this in a larger cohort using the coefficient of variation (CoV) and identify potential risk factors for higher CoV. Methods We retrospectively reviewed 351 lung transplant recipients who received tacrolimus-based immunosuppression therapy. Cox proportional hazard modeling was used to investigate the effects of mean tacrolimus and CoV levels on survival and CLAD. Results Tacrolimus CoV from 6 to 12 months was independently associated with both CLAD (hazard ratio [HR], 19.99; 95% CI, 7.55-52.91; p < 0.001) and death (HR, 14.57; 95% (confidence interval) CI, 6.08-34.90; p < 0.001). Conversely, the mean trough tacrolimus blood concentration between 6 to 12 months was not associated with an increased risk of CLAD (HR, 0.94; 95% CI, 0.84-1.06; p = 0.34) or death (HR, 0.91; 95% CI, 0.82-1.01; p = 0.07). In a multivariable model, erratic tacrolimus levels were associated with antifungal use (β 0.10 95% CI 0.54-1.51, p < 0.001) and younger age (Î2 -0.0015, 95% CI -0.17 to -0.03, p = 0.005 per 5 years). Conclusions Erratic tacrolimus levels at 6 to 12 months post-lung transplant were associated with poor lung transplant outcomes. Future studies are required to determine whether interventions designed to optimize tacrolimus CoV could improve lung transplant outcomes.
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Affiliation(s)
| | - Stephanie Yerkovich
- Queensland Lung Transplant Service, The Prince Charles Hospital, Brisbane, Australia
| | - Peter M Hopkins
- University of Queensland, Brisbane, Australia
- Queensland Lung Transplant Service, The Prince Charles Hospital, Brisbane, Australia
| | - Trish Leisfield
- Queensland Lung Transplant Service, The Prince Charles Hospital, Brisbane, Australia
| | - Lesleigh Winks
- Queensland Lung Transplant Service, The Prince Charles Hospital, Brisbane, Australia
| | - Daniel C Chambers
- University of Queensland, Brisbane, Australia
- Queensland Lung Transplant Service, The Prince Charles Hospital, Brisbane, Australia
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10
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Bilhartz JL, Lopez MJ, Eder SJ, Magee JC, Rea K, Sturza J, Fredericks EM. Changes over time in self-efficacy and the allocation of responsibility for health management tasks in pediatric liver transplant recipients: Targets to improve the transition process. Pediatr Transplant 2024; 28:e14673. [PMID: 38059409 DOI: 10.1111/petr.14673] [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: 06/14/2023] [Revised: 11/03/2023] [Accepted: 11/24/2023] [Indexed: 12/08/2023]
Abstract
BACKGROUND The process of transition to adult-based care encompasses a critical period in the life of an adolescent and young adult living with a chronic illness and one that comes with an increase in the risk of poor health outcomes. As yet, there is a dearth of empirical data to help optimize this process to ensure the best long-term outcome. METHODS This study used a principal components analysis to determine specific constructs measured by a revised version of the transition readiness survey used in our clinic. We investigated changes in these constructs over time. We further investigated the relationship between the change in these constructs over time spent in a focused transition program with adherence. RESULTS The primary component underlying our transition readiness survey for patients and parents represented self-efficacy. Time spent in the transition program was an independent predictor of change in self-efficacy (rho 0.299, p = .015); however, the magnitude of that change had no relationship to adherence. Change in parent-proxy self-efficacy was found to have a statistically significant relationship with tacrolimus standard deviation (rho -0.301, p = .026). There was disagreement identified between patient and parent responses on the survey. Neither change in patient nor parent reports of self-efficacy was found to have a relationship with post-transfer adherence. CONCLUSIONS This study reaches the novel conclusion that self-efficacy and parent-proxy self-efficacy are dynamic concepts that change over time spent in a focused transition program. The patient-parent disagreement and the relationship between parent-proxy self-efficacy and adherence stress the importance of involving parents/guardians in the transition process as well.
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Affiliation(s)
- Jacob L Bilhartz
- Department of Pediatrics, Michigan Medicine, Ann Arbor, Michigan, USA
- University of Michigan Transplant Center, Michigan Medicine, Ann Arbor, Michigan, USA
| | - M James Lopez
- Department of Pediatrics, Michigan Medicine, Ann Arbor, Michigan, USA
- University of Michigan Transplant Center, Michigan Medicine, Ann Arbor, Michigan, USA
| | - Sally J Eder
- Department of Pediatrics, Michigan Medicine, Ann Arbor, Michigan, USA
| | - John C Magee
- University of Michigan Transplant Center, Michigan Medicine, Ann Arbor, Michigan, USA
- Department of Surgery, Michigan Medicine, Ann Arbor, Michigan, USA
| | - Kelly Rea
- Department of Pediatrics, Michigan Medicine, Ann Arbor, Michigan, USA
| | - Julie Sturza
- Department of Pediatrics, Michigan Medicine, Ann Arbor, Michigan, USA
| | - Emily M Fredericks
- Department of Pediatrics, Michigan Medicine, Ann Arbor, Michigan, USA
- University of Michigan Transplant Center, Michigan Medicine, Ann Arbor, Michigan, USA
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11
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Shemesh E, Duncan-Park S, Mazariegos G, Annunziato R, Anand R, Reyes-Mugica M, Mitchell J, Shneider BL. The improving Medication Adherence in Adolescents and young adults following Liver Transplantation (iMALT) multisite trial: Design and trial implementation considerations. Clin Trials 2023; 20:528-535. [PMID: 37269062 PMCID: PMC10524899 DOI: 10.1177/17407745231176834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
BACKGROUND/AIMS Medication non-adherence is a leading cause of transplant rejection, organ loss, and death; yet no rigorous controlled study to date has shown compelling clinical benefits from an adherence-improving intervention. Non-adherent patients are less likely to participate in trials, and therefore, most studies enroll a majority of adherent patients who do not stand to benefit from the intervention, as they do not have the condition (non-adherence) under investigation. The improving Medication Adherence in adolescent Liver Transplant recipients trial specifically targets non-adherent patients to investigate whether a remote intervention to improve adherence results in reduced incidence of biopsy-confirmed rejection. METHODS Improving Medication Adherence in adolescent Liver Transplant is a randomized single-blind controlled multisite, multinational National Institutes of Health-funded trial involving 13 pediatric transplant centers in the United States and Canada. An innovative, objective adherence biomarker-the Medication Level Variability Index, which is the standard deviation of a series of medication blood levels for each patient, is used to identify non-adherent patients at risk for rejection. The index is computed using electronic health record information for all potentially eligible patients based on repeated reviews of the entire clinic's roster. Identified patients, after consent, are randomized to intervention versus control (treatment as usual) arms. The remote intervention is delivered for 2 years by trained interventionists who reside in various locations in the United States. The primary outcome is the incidence of biopsy-confirmed acute cellular rejection, as confirmed by a majority vote of three pathologists who are masked to the study allocation and clinical information. DISCUSSION Improving Medication Adherence in adolescent Liver Transplant includes several innovative design elements. The use of a validated, objective adherence index to survey a large cohort of transplant recipients allows the teams to avoid bias inherent in both convenience sampling and referral-based recruitment and enroll only patients whose computed index indicates substantially increased risk of rejection. The remote intervention paradigm helps to engage patients who are by definition hard to engage. The use of an objective, masked medical (rather than behavioral) outcome measure reduces the likelihood of biases related to clinical information and ensures broad acceptance by the field. Finally, monitoring for potential adverse events related to increased medication exposure due to the adherence intervention acknowledges that a successful intervention (increasing adherence) could have detrimental side effects via increased exposure to and potential toxicity of the medication. Such monitoring is almost never attempted in clinical trials evaluating adherence interventions.
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Affiliation(s)
- Eyal Shemesh
- Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | | | | | - Rachel Annunziato
- Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Fordham University, Bronx, NY, USA
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12
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Serper M, Burdzy A, Schaubel DE, Mason R, Banerjee A, Goldberg DS, Martin EF, Mehta SJ, Russell LB, Cheung AC, Ladner DP, Yoshino Benavente J, Wolf MS. Patient randomised controlled trial of technology enabled strategies to promote treatment adherence in liver transplantation: rationale and design of the TEST trial. BMJ Open 2023; 13:e075172. [PMID: 37723108 PMCID: PMC10510935 DOI: 10.1136/bmjopen-2023-075172] [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: 04/28/2023] [Accepted: 08/25/2023] [Indexed: 09/20/2023] Open
Abstract
BACKGROUND AND AIMS Liver transplantation is a life-saving procedure for end-stage liver disease. However, post-transplant medication regimens are complex and non-adherence is common. Post-transplant medication non-adherence is associated with graft rejection, which can have long-term adverse consequences. Transplant centres are equipped with clinical staff that monitor patients post-transplant; however, digital health tools and proactive immunosuppression adherence monitoring has potential to improve outcomes. METHODS AND ANALYSIS This is a patient-randomised prospective clinical trial at three transplant centres in the Northeast, Midwest and South to investigate the effects of a remotely administered adherence programme compared with usual care. The programme monitors potential non-adherence largely levering text message prompts and phenotypes the nature of the non-adhere as cognitive, psychological, medical, social or economic. Additional reminders for medications, clinical appointments and routine self-management support are incorporated to promote adherence to the entire medical regimen. The primary study outcome is medication adherence via 24-hour recall; secondary outcomes include additional medication adherence (ASK-12 self-reported scale, regimen knowledge scales, tacrolimus values), quality of life, functional health status and clinical outcomes (eg, days hospitalised). Study implementation, acceptability, feasibility, costs and potential cost-effectiveness will also be evaluated. ETHICS AND DISSEMINATION The University of Pennsylvania Review Board has approved the study as the single IRB of record (protocol # 849575, V.1.4). Results will be published in peer-reviewed journals and summaries will be provided to study funders. TRIAL REGISTRATION NUMBER NCT05260268.
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Affiliation(s)
- Marina Serper
- Division of Gastroenterology and Hepatology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Alexander Burdzy
- Division of Gastroenterology and Hepatology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Douglas E Schaubel
- Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Richard Mason
- Division of Gastroenterology and Hepatology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Arpita Banerjee
- Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - David S Goldberg
- Division of Digestive Health and Liver Diseases, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Eric F Martin
- Division of Digestive Health and Liver Diseases, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Shivan J Mehta
- Division of Gastroenterology and Hepatology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Louise B Russell
- Department of Medical Ethics and Health Policy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Amanda C Cheung
- Division of Gastroenterology and Hepatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Daniela P Ladner
- Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Julia Yoshino Benavente
- Center for Applied Health Research on Aging, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Michael S Wolf
- Center for Applied Health Research on Aging, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
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13
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Morais MC, Soares ME, Costa G, Guerra L, Vaz N, Codes L, Bittencourt PL. Impact of tacrolimus intra-patient variability in adverse outcomes after organ transplantation. World J Transplant 2023; 13:254-263. [PMID: 37746041 PMCID: PMC10514747 DOI: 10.5500/wjt.v13.i5.254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 07/31/2023] [Accepted: 08/11/2023] [Indexed: 09/15/2023] Open
Abstract
Tacrolimus (Tac) is currently the most common calcineurin-inhibitor employed in solid organ transplantation. High intra-patient variability (IPV) of Tac (Tac IPV) has been associated with an increased risk of immune-mediated rejection and poor outcomes after kidney transplantation. Few data are available concerning the impact of high Tac IPV in non-kidney transplants. However, even in kidney transplantation, there is still a controversy whether high Tac IPV is indeed detrimental in respect to graft and/or patient survival. This may be due to different methods employed to evaluate IPV and distinct time frames adopted to assess graft and patient survival in those reports published up to now in the literature. Little is also known about the influence of high Tac IPV in the development of other untoward adverse events, update of the current knowledge regarding the impact of Tac IPV in different outcomes following kidney, liver, heart, lung, and pancreas tran splantation to better evaluate its use in clinical practice.
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Affiliation(s)
- Maria Clara Morais
- School of Medicine, Bahiana School of Medicine and Public Health, Salvador 40290-000, Bahia, Brazil
| | - Maria Eduarda Soares
- School of Medicine, Federal University of Bahia, Salvador 40110-100, Bahia, Brazil
| | - Gabriela Costa
- School of Medicine, Bahiana School of Medicine and Public Health, Salvador 40290-000, Bahia, Brazil
| | - Laura Guerra
- School of Medicine, Bahiana School of Medicine and Public Health, Salvador 40290-000, Bahia, Brazil
| | - Nayana Vaz
- School of Medicine, Bahiana School of Medicine and Public Health, Salvador 40290-000, Bahia, Brazil
- Unit of Gastroenterology and Hepatology, Portuguese Hospital, Salvador 40130-030, Bahia, Brazil
| | - Liana Codes
- School of Medicine, Bahiana School of Medicine and Public Health, Salvador 40290-000, Bahia, Brazil
- Unit of Gastroenterology and Hepatology, Portuguese Hospital, Salvador 40130-030, Bahia, Brazil
| | - Paulo Lisboa Bittencourt
- School of Medicine, Bahiana School of Medicine and Public Health, Salvador 40290-000, Bahia, Brazil
- Unit of Gastroenterology and Hepatology, Portuguese Hospital, Salvador 40130-030, Bahia, Brazil
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14
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Sayegh CS, Im D, Moss IK, Urquiza R, Patel S, Thomas D. Randomized pilot trial of praise text messages to improve medication adherence among adolescents and young adults with liver transplants. Pediatr Transplant 2022; 26:e14361. [PMID: 35854423 PMCID: PMC9560958 DOI: 10.1111/petr.14361] [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: 12/01/2021] [Revised: 04/27/2022] [Accepted: 06/10/2022] [Indexed: 11/30/2022]
Abstract
BACKGROUND AYA who have undergone liver transplantations often struggle to adhere to their post-transplant immunosuppressant medications, which can lead to serious health complications. The objective of this pilot study is to examine the acceptability and feasibility of a brief mobile health (mHealth) intervention and its impact on medication adherence among AYA liver transplant recipients. METHODS Thirty-five AYAs (13-21 years old) were randomized to either (1) receive praise text messages whenever laboratory results indicated immunosuppressant medications within the expected range or (2) usual care. Motivation for adherence and adherence were assessed via self-report, and a MLVI was calculated based on values abstracted from the electronic health record. RESULTS Multilevel, multivariate models showed significant associations between group assignment and some self-reported motivation and adherence outcomes but not MLVI. Specifically, AYA receiving the praise text messages were significantly more likely to report taking their prescribed doses (OR = 2.49, p = .03), taking their medicine according to the directions (OR = 2.39, p = .04), and being highly confident in taking their medication (OR = 2.46, p = .04), compared with the usual services group. Qualitative responses indicated praise texts were mostly helpful but could be improved. CONCLUSIONS The results suggest texting patients about positive health indicators was acceptable and, with refinement, might promote AYA illness self-management.
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Affiliation(s)
- Caitlin S. Sayegh
- Children’s Hospital Los Angeles, Division of Adolescent and Young Adult Medicine
- Children’s Hospital Los Angeles, USC University Center for Excellence in Developmental Disabilities
- University of Southern California Keck School of Medicine
| | - Deborah Im
- University of Southern California Keck School of Medicine
| | - Ilana K. Moss
- Children’s Hospital Los Angeles, Division of Gastroenterology, Hepatology, and Nutrition
| | - Ruby Urquiza
- Children’s Hospital Los Angeles, Division of Gastroenterology, Hepatology, and Nutrition
| | - Shreena Patel
- University of Southern California Keck School of Medicine
- Children’s Hospital Los Angeles, Division of Gastroenterology, Hepatology, and Nutrition
| | - Daniel Thomas
- University of Southern California Keck School of Medicine
- Children’s Hospital Los Angeles, Division of Gastroenterology, Hepatology, and Nutrition
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15
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Morais-DE-Jesus M, Jesus-Nunes AP, Codes L, Argolo FC, Quarantini LC. MENTAL DISORDERS AND LIVER TRANSPLANTATION: A 2-YEAR COHORT STUDY. ARQUIVOS DE GASTROENTEROLOGIA 2022; 59:494-500. [PMID: 36515345 DOI: 10.1590/s0004-2803.202204000-88] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Accepted: 08/18/2022] [Indexed: 11/16/2022]
Abstract
BACKGROUND Psychosocial assessment is a key component in evaluation for liver transplantation and may affect survival rates and outcomes. OBJECTIVE The primary aim of this study was to investigate the impact of previous mental disorders and impulsivity on the 2-year surviving rate after liver transplantation. METHODS We performed a prospective cohort study assessing end-stage liver disease individuals with and without psychiatric comorbidities for 2 years post-transplant. Psychiatric diagnosis was carried out through Mini-Plus 5.0.0 and impulsivity by using Barratt Impulsiveness Scale in the pre-transplant phase. We followed patient's status for 2 years after transplantation. The main outcome was death. We used a logistic regression to evaluate the association of psychiatric comorbidities with death and performed a survival analysis with Kaplan-Meier and Cox regression models. RESULTS Between June 2010 and July 2014, 93 out of 191 transplant candidates received transplants. From the 93 transplant patients, 21 had psychiatric comorbidities and 72 had not. 25 patients died during the study. The presence of psychiatric comorbidities (P=0.353) and high impulsivity (P=0.272) were not associated to 2-year post transplant death. CONCLUSION This study found no evidence that the presence of mental disorders and impulsivity worsened prognosis in post-liver transplantation.
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Affiliation(s)
- Mychelle Morais-DE-Jesus
- Universidade Federal da Bahia, Programa de Pós-Graduação em Medicina e Saúde, Salvador, BA, Brasil
| | - Ana P Jesus-Nunes
- Universidade Federal da Bahia, Programa de Pós-Graduação em Medicina e Saúde, Salvador, BA, Brasil
| | - Liana Codes
- Universidade Federal da Bahia, Hospital Universitário Professor Edgard Santos, Serviço de Hepatologia, Salvador, BA, Brasil
| | - Felipe C Argolo
- Universidade Federal de São Paulo, Departamento de Psiquiatria, Pós-graduação de Psiquiatria e Psicologia Médica, São Paulo, SP, Brasil
| | - Lucas C Quarantini
- Universidade Federal da Bahia, Hospital Universitário Professor Edgard Santos, Laboratório de Neuropsicofarmacologia, Serviço de Psiquiatria de Salvador, Salvador, BA, Brasil
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16
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Killian MO, Clifford S, Lustria MLA, Skivington GL, Gupta D. Directly observed therapy to promote medication adherence in adolescent heart transplant recipients. Pediatr Transplant 2022; 26:e14288. [PMID: 35436376 DOI: 10.1111/petr.14288] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 03/28/2022] [Accepted: 04/01/2022] [Indexed: 12/01/2022]
Abstract
PURPOSE HT recipients experience high levels of medication non-adherence during adolescence. This pilot study examined the acceptability and feasibility of an asynchronous DOT mHealth application among adolescent HT recipients. The app facilitates tracking of patients' dose-by-dose adherence and enables transplant team members to engage patients. The DOT application allows patients to self-record videos while taking their medication and submit for review. Transplant staff review the videos and communicate with patients to engage and encourage medication adherence. METHODS Ten adolescent HT recipients with poor adherence were enrolled into a single-group, 12-week pilot study examining the impact of DOT on adherence. Secondary outcomes included self-report measures from patients and parents concerning HRQOL and adherence barriers. Long-term health outcomes assessed included AR and hospitalization 6 months following DOT. FINDINGS Among 14 adolescent HT patients approached, 10 initiated the DOT intervention. Of these, 8 completed the 12-week intervention. Patients and caregivers reported high perceptions of acceptability and accessibility. Patients submitted 90.1% of possible videos demonstrating medication doses taken. MLVI values for the 10 patients initiating DOT decreased from 6 months prior to the intervention (2.86 ± 1.83) to 6 months following their involvement (2.08 ± 0.87) representing a 21.7% decrease in non-adherence, though not statistically significant given the small sample size. CONCLUSIONS Result of this pilot study provides promising insights regarding the feasibility, acceptability, and potential impact of DOT for adolescent HT recipients. Further randomized studies are required to confirm these observations.
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Affiliation(s)
- Michael O Killian
- College of Social Work, Florida State University, Tallahassee, Florida, USA.,College of Medicine, Florida State University, Tallahassee, Florida, USA
| | - Stephanie Clifford
- Congenital Heart Center, UF Health Shands Children's Hospital, University of Florida, Gainesville, Florida, USA.,College of Nursing, University of Florida, Gainesville, Florida, USA
| | - Mia Liza A Lustria
- College of Medicine, Florida State University, Tallahassee, Florida, USA.,School of Information, College of Communication and Information, Florida State University, Tallahassee, Florida, USA
| | - Gage L Skivington
- College of Social Work, Florida State University, Tallahassee, Florida, USA
| | - Dipankar Gupta
- Congenital Heart Center, UF Health Shands Children's Hospital, University of Florida, Gainesville, Florida, USA.,Department of Pediatrics, College of Medicine, University of Florida, Gainesville, Florida, USA
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17
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Rea KE, Cushman GK, Quast LF, George RP, Basu A, Ford R, Book W, Blount RL. Initial attendance and retention in adult healthcare as criteria for transition success among organ transplant recipients. Pediatr Transplant 2022; 26:e14280. [PMID: 35388604 DOI: 10.1111/petr.14280] [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: 05/24/2021] [Revised: 03/15/2022] [Accepted: 03/26/2022] [Indexed: 11/28/2022]
Abstract
BACKGROUND Adolescent and young adult (AYA) solid organ transplant recipients experience worsening medical outcomes during transition to adult healthcare. Current understanding and definitions of transition success emphasize first initiation of appointment attendance in adult healthcare; however, declines in attendance over time after transfer remain possible, particularly as AYAs are further removed from their pediatric provider and assume greater independence in their care. METHODS The current study assessed health-care utilization, medical outcomes, and transition success among 49 AYA heart, kidney, or liver recipients recently transferred to adult healthcare. Differences in outcomes were examined along two transition success criteria: (1) initial engagement in adult healthcare within 6 or 12 months of last pediatric appointment and (2) retention in adult healthcare over 3 years following last pediatric appointment. Growth curve modeling examined change in attendance over time. RESULTS Successful retention in adult healthcare was significantly related to more improved clinical outcomes, including decreased number and duration of hospitalizations and greater medication adherence, as compared to initial engagement. Significant declines in appointment attendance over 3 years were noted, and individual differences in declines were not accounted for by age at transfer or time since transplant. CONCLUSIONS Findings underscore support for AYAs after transfer, as significant declines in attendance were noted after initiating adult care. Clinical care teams should examine transition success longitudinally to address changes in health-care utilization and medical outcomes. Attention to interventions and administrative support aimed at maintaining or increasing attendance and identifying risk factors and intervention for unsuccessful transition is warranted.
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Affiliation(s)
- Kelly E Rea
- Department of Psychology, University of Georgia, Athens, Georgia, USA
| | - Grace K Cushman
- Department of Psychology, University of Georgia, Athens, Georgia, USA.,Alpert Medical School of Brown University, Bradley/Hasbro Children's Research Center, Providence, USA
| | - Lauren F Quast
- Department of Psychology, University of Georgia, Athens, Georgia, USA
| | - Roshan P George
- Department of Pediatrics, Emory University School of Medicine, Athens, Georgia, USA
| | - Arpita Basu
- Emory Transplant Center, Emory University School of Medicine, Athens, Georgia, USA
| | - Ryan Ford
- Emory Transplant Center, Emory University School of Medicine, Athens, Georgia, USA
| | - Wendy Book
- Emory Transplant Center, Emory University School of Medicine, Athens, Georgia, USA
| | - Ronald L Blount
- Department of Psychology, University of Georgia, Athens, Georgia, USA
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18
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Dopazo C, Bilbao I, García S, Gómez-Gavara C, Caralt M, Campos-Varela I, Castells L, Hidalgo E, Moreso F, Montoro B, Charco R. High intrapatient variability of tacrolimus exposure associated with poorer outcomes in liver transplantation. Clin Transl Sci 2022; 15:1544-1555. [PMID: 35373449 PMCID: PMC9199878 DOI: 10.1111/cts.13276] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 03/03/2022] [Accepted: 03/14/2022] [Indexed: 11/29/2022] Open
Abstract
Tacrolimus (TAC) is a dose‐dependent immunosuppressor with considerable intrapatient variability (IPV) in its pharmacokinetics. The aim of this work is to ascertain the association between TAC IPV at 6 months after liver transplantation (LT) and patient outcome. This single‐center cohort study retrospectively analyzed adult patients who underwent transplantation from 2015 to 2019 who survived the first 6 months with a functioning graft. The primary end point was the patient’s probability of death and the secondary outcome was the loss of renal function between month 6 and the last follow‐up. TAC IPV was estimated by calculating the coefficient of variation (CV) of the dose‐corrected concentration (C0/D) between the third and sixth months post‐LT. Of the 140 patients who underwent LT included in the study, the low‐variability group (C0/D CV < 27%) comprised 105 patients and the high‐variability group (C0/D CV ≥ 27%) 35 patients. One‐, 3‐, and 5‐year patient survival rates were 100%, 82%, and 72% in the high‐variability group versus 100%, 97%, and 93% in the low‐variability group, respectively (p = 0.005). Moreover, significant impaired renal function was observed in the high‐variability group at 1 year (69 ± 16 ml/min/1.73 m2 vs. 78 ± 16 ml/min/1.73 m2, p = 0.004) and at 2 years post‐LT (69 ± 17 ml/min/1.73 m2 vs. 77 ± 15 ml/min/1.73 m2, p = 0.03). High C0/D CV 3–6 months remained independently associated with worse survival (hazard ratio = 3.57, 95% CI = 1.32–9.67, p = 0.012) and loss of renal function (odds ratio = 3.47, 95% CI = 1.30–9.20, p = 0.01). Therefore, high IPV between the third and sixth months appears to be an early and independent predictor of patients with poorer liver transplant outcomes.
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Affiliation(s)
- Cristina Dopazo
- Department of HPB Surgery and Transplants, Hospital Universitario Vall d´Hebron, Universidad Autónoma de Barcelona, Barcelona, Spain
| | - Itxarone Bilbao
- Department of HPB Surgery and Transplants, Hospital Universitario Vall d´Hebron, Universidad Autónoma de Barcelona, Barcelona, Spain
| | - Sonia García
- Department of Pharmacy, Barcelona Hospital Campus, Universitat Autónoma de Barcelona, Barcelona, Spain
| | - Concepción Gómez-Gavara
- Department of HPB Surgery and Transplants, Hospital Universitario Vall d´Hebron, Universidad Autónoma de Barcelona, Barcelona, Spain
| | - Mireia Caralt
- Department of HPB Surgery and Transplants, Hospital Universitario Vall d´Hebron, Universidad Autónoma de Barcelona, Barcelona, Spain
| | - Isabel Campos-Varela
- Liver Unit, Vall d'Hebron Hospital Universitari, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Universitat Autónoma de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Lluis Castells
- Liver Unit, Vall d'Hebron Hospital Universitari, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Universitat Autónoma de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Ernest Hidalgo
- Department of HPB Surgery and Transplants, Hospital Universitario Vall d´Hebron, Universidad Autónoma de Barcelona, Barcelona, Spain
| | - Francisco Moreso
- Department of Nephrology, Hospital Universitario Vall d´Hebron, Barcelona, Spain
| | - Bruno Montoro
- Department of Pharmacy, Barcelona Hospital Campus, Universitat Autónoma de Barcelona, Barcelona, Spain
| | - Ramón Charco
- Department of HPB Surgery and Transplants, Hospital Universitario Vall d´Hebron, Universidad Autónoma de Barcelona, Barcelona, Spain
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19
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Lieber SR, Kim HP, Baldelli L, Nash R, Teal R, Magee G, Desai CS, Loiselle MM, Lee SC, Singal AG, Marrero JA, Barritt AS, Evon DM. Early Survivorship After Liver Transplantation: A Qualitative Study Identifying Challenges in Recovery From the Patient and Caregiver Perspective. Liver Transpl 2022; 28:422-436. [PMID: 34529886 PMCID: PMC10548343 DOI: 10.1002/lt.26303] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 09/06/2021] [Accepted: 09/11/2021] [Indexed: 02/04/2023]
Abstract
Survivorship after liver transplantation (LT) is a novel concept providing a holistic view of the arduous recovery experienced after transplantation. We explored components of early survivorship including physical, emotional, and psychological challenges to identify intervention targets for improving the recovery process of LT recipients and caregivers. A total of 20 in-person interviews were conducted among adults 3 to 6 months after LT. Trained qualitative research experts conducted interviews, coded, and analyzed transcripts to identify relevant themes and representative quotes. Early survivorship comprises overcoming (1) physical challenges, with the most challenging experiences involving mobility, driving, dietary modifications, and medication adherence, and (2) emotional and psychological challenges, including new health concerns, financial worries, body image/identity struggles, social isolation, dependency issues, and concerns about never returning to normal. Etiology of liver disease informed survivorship experiences including some patients with hepatocellular carcinoma expressing decisional regret or uncertainty in light of their post-LT experiences. Important topics were identified that framed LT recovery including setting expectations about waitlist experiences, hospital recovery, and ongoing medication requirements. Early survivorship after LT within the first 6 months involves a wide array of physical, emotional, and psychological challenges. Patients and caregivers identified what they wish they had known prior to LT and strategies for recovery, which can inform targeted LT survivorship interventions.
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Affiliation(s)
- Sarah R. Lieber
- Division of Digestive and Liver Diseases, Department of Medicine, University of Texas Southwestern, Dallas, TX
| | - Hannah P. Kim
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
| | - Luke Baldelli
- Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC
| | - Rebekah Nash
- Department of Psychiatry, University of North Carolina School of Medicine, Chapel Hill, NC
| | - Randall Teal
- Connected Health Applications and Interventions, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Gabrielle Magee
- Center for Gastrointestinal Biology and Disease, University of North Carolina School of Medicine, Chapel Hill, NC
| | - Chirag S. Desai
- Division of Transplantation, Department of Surgery, University of North Carolina School of Medicine, Chapel Hill, NC
| | - Marci M. Loiselle
- Division of Behavioral Medicine, Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC
| | - Simon C. Lee
- Department of Population and Data Sciences, University of Texas Southwestern Medical, Dallas, TX
| | - Amit G. Singal
- Division of Digestive and Liver Diseases, Department of Medicine, University of Texas Southwestern, Dallas, TX
| | - Jorge A. Marrero
- Division of Digestive and Liver Diseases, Department of Medicine, University of Texas Southwestern, Dallas, TX
| | - A. Sidney Barritt
- Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC
| | - Donna M. Evon
- Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC
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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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21
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The Role of Intra-Patient Variability of Tacrolimus Drug Concentrations in Solid Organ Transplantation: A Focus on Liver, Heart, Lung and Pancreas. Pharmaceutics 2022; 14:pharmaceutics14020379. [PMID: 35214111 PMCID: PMC8878862 DOI: 10.3390/pharmaceutics14020379] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 02/02/2022] [Accepted: 02/05/2022] [Indexed: 11/17/2022] Open
Abstract
Tacrolimus, the keystone immunosuppressive drug administered after solid organ transplantation, presents a narrow therapeutic index and wide inter- and intra-patient pharmacokinetic variability (IPV). The latter has been fairly studied in kidney transplantation, where it could impact outcomes. However, literature about other transplanted organ recipients remains inconclusive. This review aimed at summarizing the evidence about the IPV of tacrolimus concentrations outside of the scope of kidney transplantation. First, factors influencing IPV will be presented. Then, the potential of IPV as a biomarker predictive of graft outcomes will be discussed in liver, heart, lung and pancreas transplantation. Lastly, strategies to reduce IPV will be reviewed, with the ultimate objective being ready-to-implement solutions in clinical practice by transplantation professionals.
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22
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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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23
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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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24
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Lee TY, Choi HJ, Seo CH, Ahn J, Hong TH, You YK. Steroid-Resistant Rejection in Liver Transplant: A Single-Center Study for Risk Factor and Second-Line Treatment. Transplant Proc 2022; 54:443-449. [DOI: 10.1016/j.transproceed.2021.10.019] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Accepted: 10/28/2021] [Indexed: 11/28/2022]
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25
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Briggs G, Wallace D, Flasche S, Walker K, Cowling T, Heaton N, van der Meulen J, Samyn M, Joshi D. Inferior outcomes in young adults undergoing liver transplantation - a UK and Ireland cohort study. Transpl Int 2021; 34:2274-2285. [PMID: 34486751 DOI: 10.1111/tri.14033] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 07/08/2021] [Accepted: 09/01/2021] [Indexed: 01/07/2023]
Abstract
Graft loss incidence is reported to be inversely related to recipient age. We used a national cohort of liver transplant (LT) recipients from the United Kingdom and Ireland to compare the age-dependent risk of graft failure in different post-transplantation time-periods ('epochs'). A cohort of first-time LT recipients (1995-2016) were identified (11 006). Cox regression was used to estimate hazard ratios (HR) comparing graft loss between age-groups (18-29, 30-39, 40-49, 50-59 and 60-76 years) and graft loss in different post-transplant epochs: 0-90 days, 90 days-2 years and 2-10 years. The risk of graft failure was highest in those transplanted between age 18 and 29 (adjusted HR 1.25, 95% CI: 1.00-1.57, P = 0.04) and in those aged 30-39 (adjusted HR 1.31, 95% CI: 1.11-1.55, P = 0.02). Graft failure in those under the age of 40 was similar in the first 90 days but worse 2-10 years' post-LT (18-29 years HR 1.36, 95% CI: 0.96-1.93, P < 0.001). Graft failure because of chronic rejection (CR) was more common in recipients aged 18-29 (P < 0.001). Adults transplanted between age 18 and 39 are at risk of late graft loss. CR is a concern for young adults (18-29 years). Our data highlights the need for specialist young adult services within adult healthcare.
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Affiliation(s)
- Gillian Briggs
- Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK
| | - David Wallace
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, UK.,Department of Health Services Research and Policy, London School of Hygiene and Tropical Medicine, London, UK
| | - Stefan Flasche
- Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK
| | - Kate Walker
- Department of Health Services Research and Policy, London School of Hygiene and Tropical Medicine, London, UK
| | - Thomas Cowling
- Department of Health Services Research and Policy, London School of Hygiene and Tropical Medicine, London, UK
| | - Nigel Heaton
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, UK
| | - Jan van der Meulen
- Department of Health Services Research and Policy, London School of Hygiene and Tropical Medicine, London, UK
| | - Marianne Samyn
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, UK
| | - Deepak Joshi
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, UK
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26
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Sirota M, Heyrend C, Ou Z, Masotti S, Griffiths E, Molina K. Impact of tacrolimus variability on pediatric heart transplant outcomes. Pediatr Transplant 2021; 25:e14043. [PMID: 34390091 DOI: 10.1111/petr.14043] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 03/26/2021] [Accepted: 04/05/2021] [Indexed: 11/28/2022]
Abstract
BACKGROUND Tacrolimus is a narrow therapeutic index drug, requiring consistent levels to maximize transplant success while reducing adverse effects. Elevated tacrolimus level variability (ETLV) is associated with poor outcomes in both pediatric and adult solid organ transplant recipients. We sought to describe the prevalence of ETLV and identify associations with patient-specific factors and poor outcomes. METHODS Tacrolimus levels were evaluated from 118 patients at our single center. As a marker of variability, standard deviations (SD) were calculated for each patient from their entire tacrolimus level data set (global SD), and 1-2 years and 1-5 years post-HT (prediction window SDs). SD ≥3 denoted ETLV. RESULTS There was large variability in tacrolimus levels (median global SD 3.1; IQR 2.3, 4; SD ≥3, n = 64, 54%). Patients with elevated SD (≥3) vs lower SD (<3) were more likely to have poor outcomes including rejection (73% vs 46%), cardiac allograft vasculopathy (CAV, 22% vs 9%), and death (20% vs 6%). The prediction window analysis noted ETLV was associated with a 40% greater risk of CAV, re-HT, or death (p = .024) and increasing age at transplantation was associated with a 12% increase in the risk of rejection (p = <.001) and a 19% increase in the risk of a composite event (p = .021). CONCLUSION ETLV is prevalent in the pediatric HT population with increased frequency of poor outcomes in those with SD ≥3. ETLV is an easily accessible marker with which to risk-stratify patients.
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Affiliation(s)
- Megan Sirota
- Department of Cardiology, Primary Children's Hospital, Salt Lake City, UT, USA
| | - Caroline Heyrend
- Department of Pharmacy, Primary Children's Hospital, Salt Lake City, UT, USA
| | - Zhining Ou
- Department of Internal Medicine, Division of Epidemiology, University of Utah Healthcare, Salt Lake City, UT, USA
| | - Susan Masotti
- Division of System Improvement, Primary Children's Hospital, Salt Lake City, UT, USA
| | - Eric Griffiths
- Division of Cardiothoracic Surgery, University of Utah Healthcare, Salt Lake City, UT, USA
| | - Kimberly Molina
- Department of Cardiology, Primary Children's Hospital, Salt Lake City, UT, USA
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27
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Duncan-Park S, Dunphy C, Becker J, D’Urso C, Annunziato R, Blatter J, Conrad C, Goldfarb SB, Hayes D, Melicoff E, Schecter M, Visner G, Armstrong B, Chin H, Kesler K, Williams NM, Odim JN, Sweet SC, Danziger-Isakov L, Shemesh E. Remote intervention engagement and outcomes in the Clinical Trials in Organ Transplantation in Children consortium multisite trial. Am J Transplant 2021; 21:3112-3122. [PMID: 33752251 PMCID: PMC8856090 DOI: 10.1111/ajt.16567] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 02/03/2021] [Accepted: 02/23/2021] [Indexed: 01/25/2023]
Abstract
Remote interventions are increasingly used in transplant medicine but have rarely been rigorously evaluated. We investigated a remote intervention targeting immunosuppressant management in pediatric lung transplant recipients. Patients were recruited from a larger multisite trial if they had a Medication Level Variability Index (MLVI) ≥2.0, indicating worrisome tacrolimus level fluctuation. The manualized intervention included three weekly phone calls and regular follow-up calls. A comparison group included patients who met enrollment criteria after the subprotocol ended. Outcomes were defined before the intent-to-treat analysis. Feasibility was defined as ≥50% of participants completing the weekly calls. MLVI was compared pre- and 180 days postenrollment and between intervention and comparison groups. Of 18 eligible patients, 15 enrolled. Seven additional patients served as the comparison. Seventy-five percent of participants completed ≥3 weekly calls; average time on protocol was 257.7 days. Average intervention group MLVI was significantly lower (indicating improved blood level stability) at 180 days postenrollment (2.9 ± 1.29) compared with pre-enrollment (4.6 ± 2.10), p = .02. At 180 days, MLVI decreased by 1.6 points in the intervention group but increased by 0.6 in the comparison group (p = .054). Participants successfully engaged in a long-term remote intervention, and their medication blood levels stabilized. NCT02266888.
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Affiliation(s)
- Sarah Duncan-Park
- Icahn School of Medicine at Mount Sinai, Department of Pediatrics and Kravis Children’s Hospital, New York, New York
- Fordham University, Department of Psychology, Bronx, New York
| | - Claire Dunphy
- Icahn School of Medicine at Mount Sinai, Department of Pediatrics and Kravis Children’s Hospital, New York, New York
- Fordham University, Department of Psychology, Bronx, New York
| | - Jacqueline Becker
- Icahn School of Medicine at Mount Sinai, Department of Pediatrics and Kravis Children’s Hospital, New York, New York
| | - Christine D’Urso
- Icahn School of Medicine at Mount Sinai, Department of Pediatrics and Kravis Children’s Hospital, New York, New York
| | - Rachel Annunziato
- Icahn School of Medicine at Mount Sinai, Department of Pediatrics and Kravis Children’s Hospital, New York, New York
- Fordham University, Department of Psychology, Bronx, New York
| | | | - Carol Conrad
- Lucille Packard Children’s Hospital, Palo Alto, California
| | | | - Don Hayes
- Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
| | | | - Marc Schecter
- Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
| | - Gary Visner
- Boston Children’s Hospital, Boston, Massachusetts
| | | | | | | | | | - Jonah N Odim
- National Institutes of Health, NIAID, Bethesda, Maryland
| | | | | | - Eyal Shemesh
- Icahn School of Medicine at Mount Sinai, Department of Pediatrics and Kravis Children’s Hospital, New York, New York
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28
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No Apparent Influence of Nonadherence on Tacrolimus Intrapatient Variability in Stable Kidney Transplant Recipients. Ther Drug Monit 2021; 42:702-709. [PMID: 32941396 DOI: 10.1097/ftd.0000000000000772] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND High intrapatient variability (IPV) in tacrolimus exposure has been associated with an increased risk of graft rejection and graft loss. It has been suggested that medication nonadherence has high impact on IPV. The objective of this study is to assess the relationship between tacrolimus IPV and medication nonadherence in stable kidney transplant recipients. METHODS This study was conducted within the Reducing Renal Function Deterioration trial (Netherlands Trial Register: NTR7256), which included stable kidney transplant recipients. Nonadherence was assessed quantitatively by electronic monitoring (EM) and qualitatively using the composite adherence score (CAS) consisting of patient self-reporting (Immunosuppressant Therapy Adherence Scale), a physician report, and the tacrolimus trough concentrations (C0). IPV in tacrolimus C0 and area under the concentration-time curves (AUCs) was evaluated at 5 and 3 sampling instances, respectively. RESULTS Data of 64 kidney transplant recipients (43 males, 21 females; mean age 53.6 years), mean time post-transplantation 5.4 years, were collected. Mean missed tacrolimus intake was 7% (0.3%-13.4%) based on EM, missing one intake every 2 weeks. Based on the CAS, 68.9% of the patients were categorized as nonadherent. The mean IPV was 17.9% (4.4%-65.3%) and 20.2% (2.5%-51.6%) for tacrolimus C0 and AUCs, respectively. The nonadherence data displayed a nonparametric distribution, with nonadherence scores mostly in the lower ranges. There was no significant difference in the mean IPV between adherent and nonadherent patients. There were no differences in EM, CAS, physician report, or time-in-therapeutic range, but patients with a low AUC IPV showed a slightly higher Immunosuppressant Therapy Adherence Scale score than those with a high AUC IPV (P = 0.035). CONCLUSIONS There was no apparent relationship between IPV and nonadherence in this motivated kidney transplant recipient population, with one missed tacrolimus dose every 2 weeks.
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29
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Long-term, Prolonged-release Tacrolimus-based Immunosuppression in De Novo Liver Transplant Recipients: 5-year Prospective Follow-up of Patients in the DIAMOND Study. Transplant Direct 2021; 7:e722. [PMID: 34263020 PMCID: PMC8274734 DOI: 10.1097/txd.0000000000001166] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 03/08/2021] [Accepted: 03/09/2021] [Indexed: 01/27/2023] Open
Abstract
Background Immunosuppression with calcineurin inhibitors (CNIs) is reportedly associated with risk of renal impairment in liver transplant recipients. It is believed that this can be mitigated by decreasing initial exposure to CNIs or delaying CNI introduction until 3-4 d posttransplantation. The ADVAGRAF studied in combination with mycophenolate mofetil and basiliximab in liver transplantation (DIAMOND) trial evaluated different administration strategies for prolonged-release tacrolimus (PR-T). Methods DIAMOND was a 24-wk, open-label, phase 3b trial in de novo liver transplant recipients randomized to: PR-T 0.2 mg/kg/d (Arm 1); PR-T 0.15-0.175 mg/kg/d plus basiliximab (Arm 2); or PR-T 0.2 mg/kg/d delayed until day 5 posttransplant plus basiliximab (Arm 3). In a 5-y follow-up, patients were maintained on an immunosuppressive regimen according to standard clinical practice (NCT02057484). Primary endpoint: graft survival (Kaplan-Meier analysis). Results Follow-up study included 856 patients. Overall graft survival was 84.6% and 73.5% at 1 and 5 y post transplant, respectively. Five-year rates for Arms 1, 2, and 3 were 74.7%, 71.5%, and 74.5%, respectively. At 5 y, death-censored graft survival in the entire cohort was 74.7%. Overall graft survival in patients remaining on PR-T for ≥30 d was 79.1%. Graft survival in patients who remained on PR-T at 5 y was 87.3%. Patient survival was 86.6% at 1 y and 76.3% at 5 y, with survival rates similar in the 3 treatment arms at 5 y. Estimated glomerular filtration rate at the end of the 24-wk initial study and 5 y posttransplant was 62.1 and 61.5 mL/min/1.73 m2, respectively, and was similar between the 3 treatment arms at 5 y. Overall, 18 (2.9%) patients had ≥1 adverse drug reaction, considered possibly related to PR-T in 6 patients. Conclusions In the DIAMOND study patient cohort, renal function, graft survival, and patient survival were similar between treatment arms at 5 y posttransplant.
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30
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Shemesh E. Using Medication Level Variability to Predict Posttransplant Risk. Liver Transpl 2021; 27:936-937. [PMID: 33576115 DOI: 10.1002/lt.26012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 01/25/2021] [Indexed: 01/13/2023]
Affiliation(s)
- Eyal Shemesh
- Division of Behavioral and Developmental Health, Department of Pediatrics and Kravis Children's Hospital, Icahn School of Medicine at Mount Sinai, New York, NY
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31
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Deutsch-Link S, Weinberg EM, Bittermann T, Serper M. Reply. Liver Transpl 2021; 27:938-939. [PMID: 33533537 PMCID: PMC9648906 DOI: 10.1002/lt.25999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Accepted: 01/25/2021] [Indexed: 01/13/2023]
Affiliation(s)
- Sasha Deutsch-Link
- Department of Gastroenterology and Hepatology University of
North Carolina–Chapel Hill Chapel Hill, NC
| | - Ethan M. Weinberg
- Division of Gastroenterology & Hepatology University of
Pennsylvania Perelman School of Medicine Philadelphia, PA
| | - Therese Bittermann
- Division of Gastroenterology & Hepatology University of
Pennsylvania Perelman School of Medicine Philadelphia, PA
| | - Marina Serper
- Division of Gastroenterology & Hepatology University of
Pennsylvania Perelman School of Medicine Philadelphia, PA,Leonard Davis Institute of Health Economics University of
Pennsylvania Perelman School of Medicine Philadelphia, PA
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Shapiro JM, Himes R, Khaderi S, Economides J, El-Serag HB. A multidisciplinary approach to improving transition readiness in pediatric liver transplant recipients. Pediatr Transplant 2021; 25:e13839. [PMID: 32997866 DOI: 10.1111/petr.13839] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Revised: 08/03/2020] [Accepted: 08/13/2020] [Indexed: 11/29/2022]
Abstract
The Six Core Elements of Transition have been advocated to guide transition, but little is published about their use with liver transplant patients. We started a liver transplant transition program in August 2015 using quality improvement (QI) methods and by linking the Six Core Elements of Transition to process measures. Eligible patients completed baseline transition readiness assessments (Readiness for Transition Questionnaire, RTQ), interviews with a psychologist, received focused education, and completed follow-up RTQs before transfer to adult care. Our QI goal was to improve RTQ scores by 20% prior to transfer to adult care. We also assessed continuity of care, tacrolimus levels, rejection, and retransplantation as balancing measures. Of the 24 patients who completed the transition program and were transferred to adult care, RTQ scores were available for 11 patients. Overall RTQ scores improved from 23.7 to 30.5 (+28.7%, P = .009) prior to transfer. Nearly two-thirds (63%) of patients were seen by adult transplant hepatology within 6 months, and one patient was lost to follow-up after the first adult visit. Tacrolimus-level standard deviations were <2.0 in 45% of patients in pediatric care and 72% of patients in adult care. Three patients had undergone immunosuppression withdrawal in pediatric care, with one restarted on immunosuppression prior to transfer to adult care due to late acute rejection. The Six Core Elements of Transition can be translated into patient- and system-level transition milestones to serve as potential quality metrics in the implementation of transition programs.
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Affiliation(s)
- Jordan M Shapiro
- U.S. Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service at the Center for Innovations in Quality, Effectiveness and Safety, Michael E. DeBakey VA Medical Center, Houston, TX, USA.,Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | - Ryan Himes
- Section of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Ochsner Health System, New Orleans, LA, USA
| | - Saira Khaderi
- Division of Abdominal Transplantation, Department of Surgery, Baylor College of Medicine, Houston, TX, USA
| | - Julie Economides
- Section of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Texas Children's Hospital, Houston, TX, USA
| | - Hashem B El-Serag
- U.S. Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service at the Center for Innovations in Quality, Effectiveness and Safety, Michael E. DeBakey VA Medical Center, Houston, TX, USA.,Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
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Association Between Neighborhood-level Socioeconomic Deprivation and the Medication Level Variability Index for Children Following Liver Transplantation. Transplantation 2021; 104:2346-2353. [PMID: 32032293 DOI: 10.1097/tp.0000000000003157] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Neighborhood socioeconomic deprivation is associated with adverse health outcomes. We sought to determine if neighborhood socioeconomic deprivation was associated with adherence to immunosuppressive medications after liver transplantation. METHODS We conducted a secondary analysis of a multicenter, prospective cohort of children enrolled in the medication adherence in children who had a liver transplant study (enrollment 2010-2013). Participants (N = 271) received a liver transplant ≥1 year before enrollment and were subsequently treated with tacrolimus. The primary exposure, connected to geocoded participant home addresses, was a neighborhood socioeconomic deprivation index (range 0-1, higher indicates more deprivation). The primary outcome was the medication level variability index (MLVI), a surrogate measure of adherence to immunosuppression in pediatric liver transplant recipients. Higher MLVI indicates worse adherence behavior; values ≥2.5 are predictive of late allograft rejection. RESULTS There was a 5% increase in MLVI for each 0.1 increase in deprivation index (95% confidence interval, -1% to 11%; P = 0.08). Roughly 24% of participants from the most deprived quartile had an MLVI ≥2.5 compared with 12% in the remaining 3 quartiles (P = 0.018). Black children were more likely to have high MLVI even after adjusting for deprivation (adjusted odds ratio 4.0 95% confidence interval, 1.7-10.6). CONCLUSIONS This is the first study to evaluate associations between neighborhood socioeconomic deprivation and an objective surrogate measure of medication adherence in children posttransplant. These findings suggest that neighborhood context may be an important consideration when assessing adherence. Differential rates of medication adherence may partly explain links between neighborhood factors and adverse health outcomes following pediatric liver transplantation.
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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: 34] [Impact Index Per Article: 6.8] [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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Becker JH, Shemesh E, Shenoy A, Posillico A, Knight CS, Kim SK, Florman SS, Schiano T, Annunziato RA. The Utility of a Pre-Transplant Psychosocial Evaluation in Predicting Post-Liver Transplant Outcomes. Prog Transplant 2020; 31:4-12. [PMID: 33272096 DOI: 10.1177/1526924820978605] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
BACKGROUND There is insufficient evidence about the ability of pretransplant psychosocial evaluations to predict posttransplant outcomes. While standardized assessments were developed to increase predictive validity, it is unclear whether the risk scores they yield predict outcomes. We investigated if the Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT), a scaling approach to those assessments, would have been a superior predictor than the standard psychosocial evaluation. METHODS In this retrospective study, medical records of 182 adult liver transplant recipients who were at least 1 year posttransplant and prescribed tacrolimus for immunosuppression were analyzed. Regression analyses predicted outcomes of interest, including immunosuppressant nonadherence and biopsy-proven rejection, obtained 1-year posttransplant to time of data collection. Nonadherence was determined using the medication level variability index (MLVI). RESULTS Approximately 49% of patients had MLVI > 2.5, suggestive of nonadherence, and 15% experienced rejection. SIPAT total score did not predict adherence either using the continuous (P = .70), or dichotimized score, above or below > 2.5 (P = .14), or rejection (P = 0.87). Using a SIPAT threshold (total score > 69) did not predict adherence (p = .16) nor was a superior predictor of the continuous adherence score (P = .45), MLVI > 2.5 (P = .42), or rejection (P = 0.49), than the standard evaluation. CONCLUSION Our findings suggest that the SIPAT is unable to predict 2 of the most important outcomes in this population, immunosuppressant adherence and rejection. Research efforts should attempt to evaluate the best manner to use psychosocial evaluations.
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Affiliation(s)
- Jacqueline H Becker
- Department of Medicine, 5925Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Department of Pediatrics, 5925Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Eyal Shemesh
- Department of Pediatrics, 5925Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Akhil Shenoy
- Center for Liver Disease and Transplantation, 21611Columbia University Medical Center, New York, NY, USA
| | - Ailie Posillico
- Department of Psychology, 5923Fordham University, Bronx, NY, USA
| | | | - Se-Kang Kim
- Department of Psychology, 5923Fordham University, Bronx, NY, USA
| | - Sander S Florman
- 52100Recanati/Miller Transplantation Institute/Division of Liver Disease, Mount Sinai Medical Center, New York, NY, USA
| | - Thomas Schiano
- 52100Recanati/Miller Transplantation Institute/Division of Liver Disease, Mount Sinai Medical Center, New York, NY, USA
| | - Rachel A Annunziato
- Department of Pediatrics, 5925Icahn School of Medicine at Mount Sinai, New York, NY, USA.,52100Recanati/Miller Transplantation Institute/Division of Liver Disease, Mount Sinai Medical Center, New York, NY, USA
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Jones LS, Serper M. Medication non-adherence among liver transplant recipients. CURRENT HEPATOLOGY REPORTS 2020; 19:327-336. [PMID: 33816051 PMCID: PMC8011544 DOI: 10.1007/s11901-020-00545-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 10/07/2020] [Indexed: 01/30/2023]
Abstract
PURPOSE OF REVIEW We provide an overview of the recent evidence on the prevalence, risk factors, and consequences of medication non-adherence (NA) in liver transplant (LT) recipients. RECENT FINDINGS NA in LT is associated with socio-demographic and medication-related factors, low social support, and poor health literacy. Patient-reported adherence is one of the most common methods to measure NA using validated assessments; immunosuppression (IS) drug levels and electronic monitoring may also be used. Simplification of IS regimens such as the conversion from twice daily to once daily has been shown to be safe, effective, and improves adherence. Relatively few studies have prospectively investigated NA predictors or interventions to reduce NA in LT. SUMMARY Medication non-adherence is a multi-faceted issue that is common among LT recipients and associated with adverse outcomes. NA in LT recipients warrants further study as only a few interventions have been published focused on reducing NA in LT.
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Affiliation(s)
- Lauren S. Jones
- Division of Gastroenterology and Hepatology, University of Pennsylvania Perelman School of Medicine
- Philadelphia College of Osteopathic Medicine, Philadelphia, PA
| | - Marina Serper
- Division of Gastroenterology and Hepatology, University of Pennsylvania Perelman School of Medicine
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Wang R, Wang W, Ma K, Duan X, Wang F, Huang M, Zhang W, Liang T. Variation in Tacrolimus Trough Concentrations in Liver Transplant Patients Undergoing Endoscopic Retrograde Cholangiopancreatography: A Retrospective, Observational Study. Front Pharmacol 2020; 11:1252. [PMID: 32973503 PMCID: PMC7466563 DOI: 10.3389/fphar.2020.01252] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Accepted: 07/30/2020] [Indexed: 12/16/2022] Open
Abstract
Objective High variabilities in tacrolimus (TAC) exposure are still problems that confuse physicians. TAC trough levels (TAC Cmin) fluctuated considerably after endoscopic retrograde cholangiopancreatography (ERCP) treatment in several liver transplant (LT) patients. We aimed to investigate the variation regularity of TAC Cmin post-ERCP and related factors. Methods This study was a retrospective, observational study conducted at the First Affiliated Hospital of Zhejiang University in China. From October 2017 to January 2019, 26 LT patients that received ERCP were included (73 TAC Cmin measures). The absolute difference and the variation extent in TAC Cmin pre- and post-ERCP were analyzed. Patients were divided into mild and obvious variation groups, and the differences were compared. Results The TAC Cmin in LT patients significantly increased in the first three days post-ERCP (p<0.05) and increased by more than 20% in 18 out of 26 (69.2%) patients. The mean extent of variation in TAC Cmin was 45.1% (95% confidence interval [CI]: 28.3–81.3%) and 31.4% (95% CI: 9.7–53.1%) on days 1 and 3 post-ERCP, respectively. The increasing TAC Cmin gradually returned to baseline within a week (p>0.05). The daily TAC dose and total bile acid (TBA) level were significantly higher (p<0.05) in patients with obvious variation in TAC Cmin. The differences in other demographics, clinical characteristics, variation in laboratory data, and serum amylase levels between the two groups were not significant. Conclusion The TAC Cmin significantly increased in LT patients during the first three days after ERCP, and the level returned to baseline within a week. The daily TAC dose and TBA levels may be related to this increase. Frequent drug concentration monitoring should be executed in the early phase post-ERCP, especially in patients with related factors.
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Affiliation(s)
- Rongrong Wang
- Department of Clinical Pharmacy, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Weili Wang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Kuifen Ma
- Department of Clinical Pharmacy, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Xin Duan
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Fangfang Wang
- Department of Pharmacy, Children's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Mingzhu Huang
- Department of Clinical Pharmacy, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Wei Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Tingbo Liang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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High Intrapatient Variability in Tacrolimus Exposure Is Not Associated With Immune-mediated Graft Injury After Liver Transplantation. Transplantation 2020; 103:2329-2337. [PMID: 30801539 DOI: 10.1097/tp.0000000000002680] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
BACKGROUND A high intrapatient variability (IPV) in tacrolimus exposure is associated with impaired long-term clinical outcome after kidney transplantation. It remains to be determined if this is equally detrimental for liver transplant recipients. The objective of this study was to investigate the association between IPV in tacrolimus exposure and immune-mediated graft injury after liver transplantation. METHODS For 326 liver transplant recipients, transplanted between 2000 and 2015, tacrolimus IPV was calculated from at least 5 tacrolimus trough samples obtained between months 6 and 18 after liver transplantation and expressed as the coefficient of variation. Primary composite endpoint consisted of immune-mediated graft injury (chronic rejection, biopsy proven, and suspected late acute rejection) after month 6. Secondary outcomes were the association between tacrolimus IPV on (1) loss of renal function per year of follow-up and (2) cytomegalovirus viremia after month 6. RESULTS Of the 326 included liver transplant recipients, 70 patients (21.5%) reached the primary endpoint. Median tacrolimus coefficient of variation was 28%. There was no significant difference in reaching the primary composite endpoint between the low- and high-IPV groups (P = 0.068). Model for End-Stage Liver Disease score pretransplantation and the number of acute rejections were identified as independent predictors for immune-mediated graft injury (P = 0.049 and 0.016). A higher IPV in combination with a low kidney function at baseline (estimated glomerular filtration rate < 40 mL/min) was associated with greater loss of renal function per year of follow-up (P = 0.007). Tacrolimus variability was not associated with late cytomegalovirus viremia. CONCLUSIONS High IPV in tacrolimus exposure beyond month 6 postliver transplantation was not associated with immune-mediated graft injury.
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Area Under Trough Concentrations of Tacrolimus as a Predictor of Progressive Renal Impairment After Liver Transplantation. Transplantation 2020; 103:2539-2548. [PMID: 31107827 DOI: 10.1097/tp.0000000000002760] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND Tacrolimus minimization is usually restricted to patients with pretransplant renal impairment, and this strategy could result into worse renal outcomes after liver transplantation (LT). METHODS A consecutive cohort of 455 LT patients receiving tacrolimus-based immunosuppression was studied (2008-2013). Cumulative exposure to tacrolimus was calculated as the area under curve of trough concentrations (AUCtc). Patients were stratified as tacrolimus minimization, conventional, or high exposure, according to the thresholds based in the COMMIT consensus. Estimated glomerular filtration rates (eGFR) were assessed by the Modification of Diet in Renal Disease formula (MDRD-4) up to 5 years after LT. RESULTS Seventy patients (15.4%) had pretransplant eGFR < 60 mL/min, which was associated with increased mortality rates, particularly within the first 5 years post-LT (31.4% versus 17.5%; Breslow P = 0.010). After LT, there was an abrupt eGFR decline within the first 3 months (median 18.6 mL/min; P < 0.001), further decreasing up to 12 months (additional 3 mL/min), without any improvement thereafter. According to AUCtc, 33.7% of patients received tacrolimus minimization, 44.8% conventional exposure, and 21.5% high exposure. Conventional/high exposure to tacrolimus resulted in a more pronounced eGFR decline within the first 3 months when compared with minimization (23.3 mL/min versus 9.5 mL/min; P < 0.001). This gap was even higher in patients with initially preserved renal function. Tacrolimus AUCtc was an independent predictor of eGFR decline within the first 3 months after controlling for potential confounders. CONCLUSIONS AUCtc is a surrogate of cumulative exposure to tacrolimus and may be helpful for routine dose adjustments. Tacrolimus minimization should be universally attempted after LT to preserve renal function.
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Improved Survival in Liver Transplant Patients Receiving Prolonged-release Tacrolimus-based Immunosuppression in the European Liver Transplant Registry (ELTR): An Extension Study. Transplantation 2020; 103:1844-1862. [PMID: 31343568 DOI: 10.1097/tp.0000000000002700] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND We compared, through the European Liver Transplant Registry, long-term liver transplantation outcomes with prolonged-release tacrolimus (PR-T) versus immediate-release tacrolimus (IR-T)-based immunosuppression. This retrospective analysis comprises up to 8-year data collected between 2008 and 2016, in an extension of our previously published study. METHODS Patients with <1 month follow-up were excluded; patients were propensity score matched for baseline characteristics. Efficacy measures included: univariate/multivariate analyses of risk factors influencing graft/patient survival up to 8 years posttransplantation, and graft/patient survival up to 4 years with PR-T versus IR-T. Overall, 13 088 patients were included from 44 European centers; propensity score-matched analyses comprised 3006 patients (PR-T: n = 1002; IR-T: n = 2004). RESULTS In multivariate analyses, IR-T-based immunosuppression was associated with reduced graft survival (risk ratio, 1.49; P = 0.0038) and patient survival (risk ratio, 1.40; P = 0.0215). There was improvement with PR-T versus IR-T in graft survival (83% versus 77% at 4 y, respectively; P = 0.005) and patient survival (85% versus 80%; P = 0.017). Patients converted from IR-T to PR-T after 1 month had a higher graft survival rate than patients receiving IR-T at last follow-up (P < 0.001), or started and maintained on PR-T (P = 0.019). One graft loss in 4 years was avoided for every 14.3 patients treated with PR-T versus IR-T. CONCLUSIONS PR-T-based immunosuppression might improve long-term outcomes in liver transplant recipients than IR-T-based immunosuppression.
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Takeda M, Sakamoto S, Irie R, Uchida H, Shimizu S, Yanagi Y, Abdelwahed MS, Fukuda A, Kasahara M. Late T cell-mediated rejection may contribute to poor outcomes in adolescents and young adults with liver transplantation. Pediatr Transplant 2020; 24:e13708. [PMID: 32333637 DOI: 10.1111/petr.13708] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Revised: 01/31/2020] [Accepted: 03/10/2020] [Indexed: 12/23/2022]
Abstract
Although poor long-term graft survival in LT in AYA is recognized, detailed epidemiological data are still lacking. L-TCMR may have poor outcomes. This study aimed to provide a detailed, epidemiological assessment of the association between AYA age and rejection. L-TCMR was defined in this study as TCMR with central vein or perivenular inflammation occurring later than 3 months after LT. A total of 342 patients who survived for at least 3 months after LT between 2005 and 2015 were enrolled. The AYA group (10-24 years) was compared with the C group (less than 10 years), and the incidence and outcomes of L-TCMR were analyzed. In total, 342 patients had LT; 38 of these were AYA with the mean follow-up period of 6.7 years. A total of 304 patients in C group had a mean follow-up period of 6.3 years (P = .28). The incidence of L-TCMR in AYA group was significantly higher than in C group (15.8% vs 4.6%, P = .006). The time to L-TCMR after LT was significantly shorter in AYA group (P = .01). Neither patient survival nor the incidence of non-adherence differed significantly between the groups (P = .18 and P = .89). The number of additional immunosuppressants after L-TCMR was significantly higher in the AYA group (P = .04). A high incidence of L-TCMR was observed in AYA group irrespective of non-adherence. AYA patients with L-TCMR should be followed carefully due to the poor results of post-treatment biopsy and the need for intensive immunosuppressive therapy.
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Affiliation(s)
- Masahiro Takeda
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Seisuke Sakamoto
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Rie Irie
- Department of Pathology, National Center for Child Health and Development, Tokyo, Japan
| | - Hajime Uchida
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Seiichi Shimizu
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Yusuke Yanagi
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Mohamed Sami Abdelwahed
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Akinari Fukuda
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
| | - Mureo Kasahara
- Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan
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Annunziato RA, Stuber ML, Supelana CJ, Dunphy C, Anand R, Erinjeri J, Alonso EM, Mazariegos GV, Venick RS, Bucuvalas J, Shemesh E. The impact of caregiver post-traumatic stress and depressive symptoms on pediatric transplant outcomes. Pediatr Transplant 2020; 24:e13642. [PMID: 31880384 DOI: 10.1111/petr.13642] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Revised: 11/27/2019] [Accepted: 12/05/2019] [Indexed: 11/26/2022]
Abstract
PTSS as well as symptoms of depression have been reported in children who experience a serious medical adversity as well as their caretakers. The adverse effects of PTSS, when experienced by the patients, on medical outcomes have been clearly documented. However, the impact of those symptoms, if any, when experienced by the caretakers on child outcomes has not been investigated prospectively. We evaluated whether caregiver PTSS and depression symptoms predict adherence to medications and medical outcomes in a prospective multisite study. Four hundred children participated in MALT. Caretaker PTSS were assessed by the IES and depressive symptoms by CES-D. During 2 years of follow-up, the MLVI was used to determine adherence. Centrally read, biopsy-confirmed organ rejection was the primary medical outcome. IES scores were not associated with either adherence or rejection outcomes. In contrast, there were significant correlations between CES-D (depression) scores and lower adherence, r = .13, P < .001, and a trend toward higher scores on the CES-D among those whose children had experienced rejection, 12.4 (SD = 10.9) versus 9.1 (SD = 8.6), P = .077. Caregivers' PTSS were not a risk factor for poor child outcomes in this cohort, whereas depression symptoms were associated with non-adherence and possibly increased rates of rejection. Further study can validate if caregivers' depression as opposed to PTSS confers greater risk and should be a focus during the clinical care of medically ill children.
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Affiliation(s)
- Rachel A Annunziato
- Icahn School of Medicine at Mount Sinai, New York, New York
- Fordham University, Bronx, New York
| | | | - Christina J Supelana
- Icahn School of Medicine at Mount Sinai, New York, New York
- Fordham University, Bronx, New York
| | - Claire Dunphy
- Icahn School of Medicine at Mount Sinai, New York, New York
- Fordham University, Bronx, New York
| | | | | | - Estella M Alonso
- Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois
| | - George V Mazariegos
- Hillman Center for Pediatric Transplantation, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania
| | | | - John Bucuvalas
- Icahn School of Medicine at Mount Sinai, New York, New York
| | - Eyal Shemesh
- Icahn School of Medicine at Mount Sinai, New York, New York
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McCormick AD, Schumacher KR, Zamberlan M, Uzark K, Yu S, Lowery R, Rottach N, Cousino MK. Generalized and specific anxiety in adolescents following heart transplant. Pediatr Transplant 2020; 24:e13647. [PMID: 31885147 DOI: 10.1111/petr.13647] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Revised: 11/26/2019] [Accepted: 12/09/2019] [Indexed: 12/18/2022]
Abstract
Mental health concerns are associated with worse outcomes after adult heart transplant. Illness-specific anxiety is associated with worsened psychological well-being after other solid organ transplants but has never been characterized after pediatric heart transplant. This single-center cross-sectional study aimed to evaluate illness-specific and generalized anxiety after heart transplantation in adolescents. A novel 12-item PHTF, GAD-7, and the PedsQL were administered. Univariate associations of demographics, clinical features, and medication adherence as measured by immunosuppression standard deviation with the PHTF and GAD-7 scores were evaluated. Internal consistency and validity of the PHTF were examined. In total, 30 patients participated. The most common illness-specific fears were retransplantation, rejection, and more generally post-transplant complications. The PHTF had good internal consistency (Cronbach α = .88). Construct validity was demonstrated between PHTF and GAD-7 (r = .62) and PedsQL (r = -.54 to -.62). 23% endorsed moderate to severe generalized anxiety symptoms. More severe symptoms were associated with older age at survey (P = .03), older age at listing (P = .01) and having post-transplant complications (P = .004). Patients with moderate or severe symptoms were more likely to report late immunosuppression doses (P = .004). Illness-specific and generalized anxiety may be prevalent after pediatric heart transplant. Screening for anxiety in adolescents post-transplant may identify those at risk for adverse outcomes including non-adherence. The PHTF is a brief, valid, and reliable instrument identifying illness-specific anxiety in this population.
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Affiliation(s)
| | - Kurt R Schumacher
- Department of Pediatrics, Michigan Medicine, Ann Arbor, Michigan.,University of Michigan Transplant Center, Ann Arbor, Michigan
| | - Mary Zamberlan
- Department of Pediatrics, Michigan Medicine, Ann Arbor, Michigan
| | - Karen Uzark
- Department of Pediatrics, Michigan Medicine, Ann Arbor, Michigan
| | - Sunkyung Yu
- Department of Pediatrics, Michigan Medicine, Ann Arbor, Michigan
| | - Ray Lowery
- Department of Pediatrics, Michigan Medicine, Ann Arbor, Michigan
| | - Nichole Rottach
- Department of Pediatrics, Michigan Medicine, Ann Arbor, Michigan
| | - Melissa K Cousino
- Department of Pediatrics, Michigan Medicine, Ann Arbor, Michigan.,University of Michigan Transplant Center, Ann Arbor, Michigan
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Campagna BR, Weatherley K, Shemesh E, Annunziato RA. Adherence to Medication During Transition to Adult Services. Paediatr Drugs 2020; 22:501-509. [PMID: 32889685 PMCID: PMC7474320 DOI: 10.1007/s40272-020-00414-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
The transition from childhood and adolescence to adulthood is often tumultuous. For individuals with a chronic medical condition, this progression also includes a gradual transition to independence in healthcare management as well as a transfer in care location at some set point. As adolescents navigate these sometimes challenging processes, there is a significant risk for a decline in adequate health behaviors, which can have dire consequences. One of the most vital components of the transfer to adult care is medication adherence. Poor medication adherence puts patients at risk for worse outcomes, with the most profound being increased mortality for many conditions. In recent years, acknowledgment of the need to create evidence-based methods to aid patients during the transition period has been growing. This paper seeks to provide an overview of current research and recommendations for interventions to increase adherence to medication regimens during this period.
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Affiliation(s)
- Bianca R. Campagna
- grid.256023.0000000008755302XDepartment of Psychology, Fordham University, 441 E. Fordham Road, Bronx, NY 10458 USA ,grid.59734.3c0000 0001 0670 2351Department of Pediatrics, Icahn School of Medicine at Mount Sinai, Kravis Children’s Hospital, New York, NY USA
| | - Kristen Weatherley
- grid.59734.3c0000 0001 0670 2351Department of Pediatrics, Icahn School of Medicine at Mount Sinai, Kravis Children’s Hospital, New York, NY USA
| | - Eyal Shemesh
- grid.59734.3c0000 0001 0670 2351Department of Pediatrics, Icahn School of Medicine at Mount Sinai, Kravis Children’s Hospital, New York, NY USA
| | - Rachel A. Annunziato
- grid.256023.0000000008755302XDepartment of Psychology, Fordham University, 441 E. Fordham Road, Bronx, NY 10458 USA ,grid.59734.3c0000 0001 0670 2351Department of Pediatrics, Icahn School of Medicine at Mount Sinai, Kravis Children’s Hospital, New York, NY USA
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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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Posttransplant Calcineurin Inhibitors Levels and Intrapatient Variability Are Not Associated With Long-term Outcomes Following Liver Transplantation. Transplantation 2019; 104:1201-1209. [PMID: 31609904 DOI: 10.1097/tp.0000000000002987] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND There is an interest in understanding the association between early calcineurin inhibitors exposure post-liver transplantation (LT) and long-term outcomes. We aimed to analyze this association exploring median calcineurin inhibitor levels and intrapatient variability (IPV) in a multicenter, retrospective cohort. METHODS Tacrolimus (Tac) and Cyclosporine (CsA) levels obtained during the first 15 days post-LT were collected. High immunosuppression (IS) was considered as a median of Tac, CsA blood trough levels 12 hours after drug administration, or blood levels 2 hours after drug administration higher than 10, 250, or 1200 ng/mL, respectively, or a peak of Tac >20 ng/mL. Optimal IS was defined as a median of Tac, CsA blood trough levels 12 hours after drug administration, or blood levels 2 hours after drug administration levels between 7 and 10, 150 and 250, or 800 and 1200 ng/mL. Low IS was defined as below the thresholds of optimal IS. IPV was estimated during the first 15 days post-LT. RESULTS The study included 432 patients with a median follow-up of 8.65 years. IS regimen was based on either Tac or CsA in 243 (56.3%) and 189 (43.8%), respectively. There were no differences in terms of graft loss among low versus optimal and high IS groups (P = 0.812 and P = 0.451) nor in high versus low IPV (P = 0.835). Only viral hepatitis and arterial hypertension were independently associated with higher graft loss (hazard ratio = 1.729, P = 0.029 and hazard ratio = 1.570, P = 0.021). CONCLUSIONS In contrast to what has previously been reported, no association was found between very early postoperative over IS or high IPV and long-term outcome measures following LT. Strategies aimed at reducing these long-term events should likely focus on other factors or on a different IS time window.
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Kuypers DRJ. Intrapatient Variability of Tacrolimus Exposure in Solid Organ Transplantation: A Novel Marker for Clinical Outcome. Clin Pharmacol Ther 2019; 107:347-358. [PMID: 31449663 DOI: 10.1002/cpt.1618] [Citation(s) in RCA: 79] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Accepted: 08/14/2019] [Indexed: 12/12/2022]
Abstract
The calcineurin-inhibitor tacrolimus (Tac) provides an acceptable balance between prevention of allograft rejection and drug-related adverse effects, making it the standard of care in all types of solid organ transplantation for the last 2 decades. Recent data have demonstrated that high intrapatient variability (IPV) in Tac predose trough concentrations has deleterious effects on allograft survival. The underlying mechanisms by which a high Tac IPV shortens allograft survival are acute and chronic rejection, donor-specific anti-HLA antibodies, and progressive fibrotic damage to the graft. Modifiable causes of high Tac IPV include medication nonadherence (MNA), drug interactions, nutritional interferences, and concurrent diseases. Recognizing high Tac IPV as an important prognostic risk factor after solid organ transplantation requires understanding of the definitions, the use of correct diagnostic metrics, and methodology. Therapeutic interventions aimed at reducing Tac IPV are targeted on improving MNA, avoiding or adjusting drug interactions, drug dosing assists, and educational support of recipients.
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Affiliation(s)
- Dirk R J Kuypers
- Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.,Department of Microbiology and Immunology, Catholic University of Leuven, Leuven, Belgium
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Gokoel SRM, Gombert-Handoko KB, Zwart TC, van der Boog PJM, Moes DJAR, de Fijter JW. Medication non-adherence after kidney transplantation: A critical appraisal and systematic review. Transplant Rev (Orlando) 2019; 34:100511. [PMID: 31627978 DOI: 10.1016/j.trre.2019.100511] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2019] [Revised: 08/27/2019] [Accepted: 08/28/2019] [Indexed: 10/26/2022]
Abstract
Medication non-adherence is one of the most important causes for shortened graft survival subsequently leading to a reduction in kidney graft survival results. Our aim was to provide an overview of its prevalence, risk factors, diagnostic methods and interventions to improve adherence in kidney transplant recipients. Therefore, we systematically searched the databases PubMed, COCHRANE Library, Web of Science and EMBASE for studies addressing "medication adherence", "compliance", "adherence", "kidney transplantation" and "life style factors". We identified 96 studies that satisfied our inclusion criteria. A problematic lack of a uniformly accepted definition for non-adherence was found, consequently leading to a wide range in non-adherence prevalence (36-55%). Using one uniformly accepted non-adherence definition should therefore be encouraged. A wide range in diagnostic methods makes it difficult to accurately detect non-adherence. Heterogeneous results of intervention studies make it difficult to select the best adherence enhancing method, challenging the battle against medication non-adherence. Literature suggests a combination of personalized interventions, based on patient-specific non-adherent behavior, to be most successful in improvement of adherence. High quality diagnostic methods and multidisciplinary, personalized interventions with focus on relevant clinical outcome are essential in overcoming medication non-adherence in kidney transplant recipients.
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Affiliation(s)
- Sumit R M Gokoel
- Division of Nephrology, Department of Medicine, Leiden University Medical Center, Leiden, the Netherlands.
| | - Kim B Gombert-Handoko
- Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, the Netherlands
| | - Tom C Zwart
- Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, the Netherlands
| | - Paul J M van der Boog
- Division of Nephrology, Department of Medicine, Leiden University Medical Center, Leiden, the Netherlands
| | - Dirk Jan A R Moes
- Department of Clinical Pharmacy & Toxicology, Leiden University Medical Center, Leiden, the Netherlands
| | - Johan W de Fijter
- Division of Nephrology, Department of Medicine, Leiden University Medical Center, Leiden, the Netherlands
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Skeens MA, Dietrich MS, Ryan-Wenger N, Gilmer MJ, Mulvaney SA, Akard TF. The Medication Level Variability Index (MLVI) as a potential predictive biomarker of graft-versus-host disease in pediatric hematopoietic stem cell transplant patients. Pediatr Transplant 2019; 23:e13451. [PMID: 31066981 DOI: 10.1111/petr.13451] [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: 10/05/2018] [Revised: 02/25/2019] [Accepted: 03/19/2019] [Indexed: 01/01/2023]
Abstract
The purpose of this study was to examine the potential predictive value of the Medication Level Variability Index (MLVI) biomarker with graft-versus-host disease (GVHD) in the pediatric hematopoietic stem cell transplant (HSCT) patient during the acute phase post-transplant. This retrospective descriptive study evaluated a total of 406 tacrolimus levels in 64 patients over a varying number of weeks per participant (median = 8, min = 3, max = 11). Patients were followed until Day 100 post-transplant or tacrolimus taper began. A total of 72 episodes of non-therapeutic levels occurred during the acute phase. Of those, 40 (56%) were <5, while 32 (44%) were >15. Approximately 39% (n = 25 of 64) of the participants in the study developed GVHD post-discharge. Those with GVHD had a statistically significantly higher MLVI than those that did not (median = 3.1, IQR = 2.5-4.7 vs 2.3, IQR = 1.6-3.4, respectively, P = 0.024). Using a criterion of MLVI > 3, there was a statistically significant increased likelihood of GVHD (OR = 3.82, 95% CI=1.32 = 11.04, P = 0.013). Area under the curve (AUC) calculation for the sensitivity and specificity of using the MLVI for GVHD was also conducted. The AUC of 0.67 was statistically significant (95% CI 0.53-0.81, P = 0.024). This is the first-known study to report the use of the MLVI in HSCT patients. The MLVI is associated with a main adverse outcome related to HSCT, GVHD. These results are encouraging of a new potential biomarker to evaluate tacrolimus serum assay levels and identify patients at risk for developing GVHD.
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Affiliation(s)
- Micah A Skeens
- Vanderbilt University School of Nursing, Nashville, Tennessee.,Nationwide Children's Hospital, Columbus, Ohio
| | - Mary S Dietrich
- Vanderbilt University School of Nursing, Nashville, Tennessee.,Vanderbilt University School of Medicine (Biostatistics, Ingram Cancer Center, Psychiatry), Nashville, Tennessee
| | | | - Mary Jo Gilmer
- Vanderbilt University School of Nursing, Nashville, Tennessee
| | - Shelagh A Mulvaney
- Vanderbilt University School of Nursing, Nashville, Tennessee.,Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee.,Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee
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Kim MS, Joh JW, Kim DS, Kim SH, Choi JS, Lee J, Lee JY, Kim JM, Kwon CHD, Choi GS, Yu YD, Yoon YI, Han JH, Lee YJ, Jiang H, Kim SI. Efficacy and safety of prolonged-release versus immediate-release tacrolimus in de novoliver transplant recipients in South Korea: a randomized open-label phase 4 study (MAPLE). KOREAN JOURNAL OF TRANSPLANTATION 2019; 33:20-29. [PMID: 35769149 PMCID: PMC9186832 DOI: 10.4285/jkstn.2019.33.2.20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 03/27/2019] [Accepted: 03/31/2019] [Indexed: 11/05/2022] Open
Abstract
Background Prolonged-release tacrolimus is associated with better long-term graft and patient survival than the immediate-release formulation in liver transplant patients. However, no clinical data are available to assess the efficacy and safety of early conversion from twice-daily, immediate-release tacrolimus to once-daily, prolonged-release tacrolimus in de novo liver transplant recipients in Korea. Methods A 24-week, randomized, open-label study was conducted in 36 liver transplant recipients. All patients received immediate- release tacrolimus (0.1–0.2 mg/kg/day, divided into two doses) for 4 weeks after transplantation, at which time 50% of the patients were converted, at a ratio of 1 mg to 1 mg, to prolonged-release tacrolimus (once-daily). The primary efficacy endpoint was the incidence of biopsy-confirmed acute rejection (BCAR) from weeks 4 to 24 after transplantation (per-protocol set). Medication adherence, adverse event profiles, laboratory tests, vital signs, and physical changes were also recorded. Results BCAR frequency at 24 weeks was similar between the two treatment groups; two cases (mean±standard deviation, 0.14±0.53 cases) of BCAR were reported in one patient treated with prolonged-release tacrolimus (n=14), while no such cases were reported among patients treated with immediate-release tacrolimus (n=12). The tacrolimus blood concentration at weeks 12 and 24, medication adherence, and adverse event profiles were also similar between the formulations, with no unusual laboratory test results, vital signs, or physical changes reported. Conclusions Early conversion to a simplified, once-daily, prolonged-release tacrolimus regimen may be an effective treatment option for liver transplant recipients in Korea. Larger-scale studies are warranted to confirm non-inferiority to immediate-release tacrolimus formulation in de novo liver transplant recipients.
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Affiliation(s)
- Myoung Soo Kim
- Department of Transplant Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Jae-Won Joh
- Department of Surgery, Samsung Medical Center, Seoul, Korea
| | - Dong-Sik Kim
- Department of Surgery, Korea University College of Medicine, Seoul, Korea
| | - Seoung Hoon Kim
- Department of Hepatobiliary Surgery, National Cancer Center, Seoul, Korea
| | - Jin Sub Choi
- Department of Hepatobiliary-Pancreas Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Jaegeun Lee
- Department of Transplant Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Jee Youn Lee
- Department of Surgery, Kangbuk Samsung Hospital, Seoul, Korea
| | - Jong Man Kim
- Department of Surgery, Samsung Medical Center, Seoul, Korea
| | | | - Gyu-Seong Choi
- Department of Surgery, Samsung Medical Center, Seoul, Korea
| | - Young Dong Yu
- Department of Hepatobiliary Surgery, Korea University Anam Hospital, Seoul, Korea
| | - Yong-In Yoon
- Department of Hepatobiliary Surgery, Asan Medical Center, Seoul, Korea
| | - Jae Hyun Han
- Department of Surgery, St. Vincent's Hospital, The Catholic University of Korea, Seoul, Korea
| | | | | | - Soon-Il Kim
- Department of Transplant Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
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