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van Gelder T, Gelinck A, Meziyerh S, de Vries APJ, Moes DJAR. Therapeutic drug monitoring of tacrolimus after kidney transplantation: trough concentration or area under curve-based monitoring? Br J Clin Pharmacol 2025; 91:1600-1606. [PMID: 38844792 PMCID: PMC12122127 DOI: 10.1111/bcp.16098] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 04/14/2024] [Accepted: 04/25/2024] [Indexed: 06/01/2025] Open
Abstract
Measurement of pre-dose tacrolimus concentrations, also referred to as trough concentrations or C0 (in this paper the term C0 will be used), is the most frequently used parameter for therapeutic drug monitoring in patients after solid organ transplantation. C0 is relatively easy to obtain, and can be combined with other lab tests. C0 monitoring is convenient for patient and hospital staff. Adjusting the dose based on C0 assumes that the C0 has a good correlation with the overall exposure to the drug, as reflected in the area under concentration-time curve (AUC). However, C0 may not be the panacea it is suggested to be, and there are patients who may benefit from additional measurements to more precisely assess drug exposure. Especially in patients with a low C0/dose ratio, the peak tacrolimus concentrations after oral administration may be unexpectedly high, resulting in toxicity and (as has been shown already) in poor long-term graft survival. At the other extreme, patients who only need a very low dose to reach target C0 may have a low peak and also a low AUC and may be underexposed. In this paper, the limitations of C0 will be discussed, and the type of studies needed to provide the evidence for implementation of more sophisticated therapeutic drug monitoring. The paper focuses on treatment of adult kidney transplant recipients.
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Affiliation(s)
- Teun van Gelder
- Department of Clinical Pharmacy & ToxicologyLeiden University Medical CenterLeidenThe Netherlands
- Leiden Transplant CenterLeiden University Medical CenterLeidenThe Netherlands
| | - Armin Gelinck
- Department of Internal Medicine, Division of NephrologyLeiden University Medical CenterLeidenThe Netherlands
- Leiden Transplant CenterLeiden University Medical CenterLeidenThe Netherlands
| | - Soufian Meziyerh
- Department of Internal Medicine, Division of NephrologyLeiden University Medical CenterLeidenThe Netherlands
- Leiden Transplant CenterLeiden University Medical CenterLeidenThe Netherlands
| | - Aiko P. J. de Vries
- Department of Internal Medicine, Division of NephrologyLeiden University Medical CenterLeidenThe Netherlands
- Leiden Transplant CenterLeiden University Medical CenterLeidenThe Netherlands
| | - Dirk Jan A. R. Moes
- Department of Clinical Pharmacy & ToxicologyLeiden University Medical CenterLeidenThe Netherlands
- Leiden Transplant CenterLeiden University Medical CenterLeidenThe Netherlands
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Qin Y, Li Y, Feng T, Pan H, Li J, Zhang F, Liu Y, Qiu J, Sun B. Correlation of renal function with intra-patient variability of tacrolimus concentration among recipients of renal transplants: a 10-year study. Transl Androl Urol 2025; 14:220-227. [PMID: 40114823 PMCID: PMC11921183 DOI: 10.21037/tau-24-564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Accepted: 01/21/2025] [Indexed: 03/22/2025] Open
Abstract
Background Tacrolimus is one of the most commonly used basic immunosuppressants nowadays, but the high variability of tacrolimus blood concentration often leads to kidney transplant recipients frequently experiencing drug concentrations above or below the target concentration, resulting in renal toxicity or rejection of the transplanted kidney. The aim of this study is to explore the correlation of renal function with intra-patient variability (IPV) of tacrolimus blood concentration among recipients of renal transplants at 1-, 3-, 5-, and 10-year post-transplantation. Methods Recipients of renal transplants who were treated with tacrolimus for immunosuppression at the Shanghai General Hospital between January 2001 and December 2009, and followed up until 2019 were included in this retrospective study. Demographic characteristics and laboratory investigation results at their 1-, 3-, 5-, and 10-year follow-up visits were collected from their hospital medical records. Patients were divided into a low or high IPV group based on the IPV of their tacrolimus concentrations. Results A total of 167 kidney transplant recipients were included in the study. At the 3-year follow-up visit, patients in the low IPV group had significantly lower blood urea nitrogen (BUN) (6.3±1.8 vs. 8.2±6.2 µmol/L, P=0.04), serum creatinine (Scr) (88.8±23.6 vs. 104.8±39.6 µmol/L, P=0.009), and blood uric acid (UA) (329.1±80.2 vs. 375.9±95.1 µmol/L, P=0.004), as well as significantly higher estimated glomerular filtration rate (eGFR) values than patients in the high IPV group. Blood UA levels were significantly lower in patients in the low IPV group than the high IPV group at the 10-year follow-up (362.7±92.6 vs. 398.5±105.2 µmol/L, P=0.042). There was no significant difference between the low and high IPV groups with respect to BUN, Scr, UA, or eGFR at the 1- and 5-year follow-up. Conclusions Recipients of renal transplants with lower IPV in tacrolimus concentration appeared to have better renal function over time. Controlling IPV may contribute to improved renal outcomes post-transplantation.
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Affiliation(s)
- Yan Qin
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yao Li
- Clinical Center for Intelligent Rehabilitation Research, Shanghai Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Center), School of Medicine, Tongji University, Shanghai, China
| | - Tienan Feng
- Clinical Research Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hui Pan
- Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiayong Li
- Laboratory Medical Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Fang Zhang
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yong Liu
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jianxin Qiu
- Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Bo Sun
- Shanghai Center for Drug Evaluation and Inspection, Shanghai, China
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Béland MA, Lapointe I, Côté I, Lesage J, Houde I, Wagner E, Riopel J, Latulippe E, Désy O, De Serres SA. HLA class, calcineurin inhibitor levels, and the risk of graft failure in kidney recipients with de novo donor-specific antibodies. Front Immunol 2024; 15:1493878. [PMID: 39635538 PMCID: PMC11614807 DOI: 10.3389/fimmu.2024.1493878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Accepted: 10/30/2024] [Indexed: 12/07/2024] Open
Abstract
Introduction De novo donor-specific HLA antibody (dnDSA) are associated with poor outcomes. Whether this observation applies to both HLA class I and II dnDSA remains unclear. Methods We studied 1236 consecutive kidney recipients who had routine anti-HLA antibody surveillance post-transplant. Results During the screening period, 55/1236 (4.4%) patients developed dnDSA: 18 (33%) HLA-I only, 33 (60%) HLA-II only, and 4 (7%) both classes. Thirty patients experienced graft loss at a median of 39 months after dnDSA detection: 9/18 (50%) HLA-I only, 17/33 (52%) HLA-II only, and 4/4 (100%) both classes. A control group was created by matching patients with dnDSA to patients who did not develop DSA and had a functioning graft at the time of dnDSA detection in their respective cases. Compared with these controls, the risk estimates of graft loss were similar between patients with HLA-I only and HLA-II only dnDSA (aHR [95% CI] 2.7 [1.1-6.6], p=0.04 and 3.1 [1.5-6.6], p<0.01 respectively). Additionally, the risk of graft loss decreased with increasing CNI trough levels following dnDSA detection (aHR 0.7 [0.6-0.9] for each increase in 1 ng/mL, p=0.02). Conclusions The prognosis of patients with dnDSA is similar regardless of the HLA class specificity. Lower calcineurin inhibitor levels predict graft loss in such patients.
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Affiliation(s)
- Marc-Antoine Béland
- Transplantation Unit, Renal Division, Department of Medicine, University Health Center (CHU) of Quebec, Faculty of Medicine, Laval University, Quebec, QC, Canada
| | - Isabelle Lapointe
- Transplantation Unit, Renal Division, Department of Medicine, University Health Center (CHU) of Quebec, Faculty of Medicine, Laval University, Quebec, QC, Canada
| | - Isabelle Côté
- Transplantation Unit, Renal Division, Department of Medicine, University Health Center (CHU) of Quebec, Faculty of Medicine, Laval University, Quebec, QC, Canada
| | - Julie Lesage
- Transplantation Unit, Renal Division, Department of Medicine, University Health Center (CHU) of Quebec, Faculty of Medicine, Laval University, Quebec, QC, Canada
| | - Isabelle Houde
- Transplantation Unit, Renal Division, Department of Medicine, University Health Center (CHU) of Quebec, Faculty of Medicine, Laval University, Quebec, QC, Canada
| | - Eric Wagner
- Immunology and Histocompatibility Laboratory, University Health Center (CHU) of Quebec, Faculty of Medicine, Laval University, Quebec, QC, Canada
| | - Julie Riopel
- Department of Pathology, University Health Center (CHU) of Quebec, Faculty of Medicine, Laval University, Quebec, QC, Canada
| | - Eva Latulippe
- Department of Pathology, University Health Center (CHU) of Quebec, Faculty of Medicine, Laval University, Quebec, QC, Canada
| | - Olivier Désy
- Transplantation Unit, Renal Division, Department of Medicine, University Health Center (CHU) of Quebec, Faculty of Medicine, Laval University, Quebec, QC, Canada
| | - Sacha A. De Serres
- Transplantation Unit, Renal Division, Department of Medicine, University Health Center (CHU) of Quebec, Faculty of Medicine, Laval University, Quebec, QC, Canada
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Baghai Arassi M, Feißt M, Krupka K, Awan A, Benetti E, Düzova A, Guzzo I, Kim JJ, Kranz B, Litwin M, Oh J, Büscher A, Pape L, Peruzzi L, Shenoy M, Testa S, Weber LT, Zieg J, Höcker B, Fichtner A, Tönshoff B, Cooperative European Pediatric Renal Transplant Initiative Research Network. Age-Related Differences in Rejection Rates, Infections, and Tacrolimus Exposure in Pediatric Kidney Transplant Recipients in the CERTAIN Registry. Kidney Int Rep 2024; 9:3265-3277. [PMID: 39534206 PMCID: PMC11551099 DOI: 10.1016/j.ekir.2024.08.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 08/20/2024] [Accepted: 08/27/2024] [Indexed: 11/16/2024] Open
Abstract
Introduction Data on age-related differences in rejection rates, infectious episodes, and tacrolimus exposure in pediatric kidney transplant recipients (pKTRs) on a tacrolimus-based immunosuppressive regimen are scarce. Methods We performed a large-scale analysis of 802 pKTRs from the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) registry from 40 centers in 14 countries. The inclusion criteria were a tacrolimus-based immunosuppressive regimen and at least 2 years of follow-up. The patient population was divided into 3 age groups (infants and young children aged <6 years, school-aged children 6-12 years, and adolescents aged >12 years) to assess age-related differences in outcome. Results Median follow-up was 48 months (interquartile range [IQR], 36-72). Within the first 2 years posttransplant, infants, and young children had a significantly higher incidence of infections (80.6% vs. 55.0% in adolescents, P < 0.001) and a significantly higher number of cumulative hospital days (median 13 days vs. 7 days in adolescents, P < 0.001). Adolescents had a significantly higher rate of biopsy-proven acute rejection episodes in the first-year posttransplant (21.7%) than infants and young children (12.6%, P = 0.007). Infants and young children had significantly lower tacrolimus trough levels, lower tacrolimus concentration-to-dose (C/D) ratios as an approximation for higher tacrolimus clearance, and higher tacrolimus interpatient variability (TacIPV) (all P < 0.01) than adolescents. Conclusion This is the largest study to date in European pKTRs on a tacrolimus-based immunosuppressive regimen, and it shows important age-related differences in rejection rates, infection episodes, as well as tacrolimus exposure and clearance. This data suggests that immunosuppressive therapy in pKTRs should be tailored and personalized according to the age-specific risk profiles of this heterogeneous patient population. The data may serve as a benchmark for future studies with novel immunosuppressive drugs.
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Affiliation(s)
- Maral Baghai Arassi
- Department of Pediatrics I, Medical Faculty, Heidelberg University, University Children’s Hospital Heidelberg, Heidelberg, Germany
- Structural and Computational Biology Unit, European Molecular Biology Laboratory Heidelberg, Heidelberg, Germany
| | - Manuel Feißt
- Institute of Medical Biometry, Heidelberg University, Heidelberg, Germany
| | - Kai Krupka
- Department of Pediatrics I, Medical Faculty, Heidelberg University, University Children’s Hospital Heidelberg, Heidelberg, Germany
| | - Atif Awan
- National Pediatric Haemodialysis Centre and Renal Transplant Unit, Temple Street Children’s University Hospital, Dublin, Ireland
| | - Elisa Benetti
- Pediatric Nephrology Unit, Department of Women’s and Children’s Health, Padua University Hospital, Italy
| | - Ali Düzova
- Division of Pediatric Nephrology, Hacettepe University Faculty of Medicine, Ankara, Türkiye
| | - Isabella Guzzo
- Division of Nephrology, Dialysis and Transplant Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
| | - Jon Jin Kim
- Department of Pediatric Nephrology, Nottingham University Hospitals, Nottingham, UK
| | - Birgitta Kranz
- Department of General Pediatrics, University Children’s Hospital Münster, Münster, Germany
| | - Mieczysław Litwin
- Department of Nephrology, Kidney Transplantation and Hypertension, The Children's Memorial Health Institute, Warsaw, Poland
| | - Jun Oh
- Division of Pediatric Nephrology, University Hamburg-Eppendorf, Hamburg, Germany
| | - Anja Büscher
- Department of Pediatrics II, University Hospital of Essen, Essen, Germany
| | - Lars Pape
- Department of Pediatrics II, University Hospital of Essen, Essen, Germany
| | - Licia Peruzzi
- Pediatric Nephrology Unit, Regina Margherita Department, Azienda Ospedaliero-Universitaria Città Della Salute e della Scienza, Torino, Italy
| | - Mohan Shenoy
- Department of Pediatric Nephrology, Royal Manchester Children's Hospital, Manchester, UK
| | - Sara Testa
- Pediatric Nephrology Unit, Dialysis and Transplantation Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Lutz T. Weber
- Pediatric Nephrology, Children's and Adolescents' Hospital, University Hospital of Cologne, Faculty of Medicine, University of Cologne, Köln, Germany
| | - Jakub Zieg
- Department of Pediatrics, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic
| | - Britta Höcker
- Department of Pediatrics I, Medical Faculty, Heidelberg University, University Children’s Hospital Heidelberg, Heidelberg, Germany
| | - Alexander Fichtner
- Department of Pediatrics I, Medical Faculty, Heidelberg University, University Children’s Hospital Heidelberg, Heidelberg, Germany
| | - Burkhard Tönshoff
- Department of Pediatrics I, Medical Faculty, Heidelberg University, University Children’s Hospital Heidelberg, Heidelberg, Germany
| | - Cooperative European Pediatric Renal Transplant Initiative Research Network
- Department of Pediatrics I, Medical Faculty, Heidelberg University, University Children’s Hospital Heidelberg, Heidelberg, Germany
- Structural and Computational Biology Unit, European Molecular Biology Laboratory Heidelberg, Heidelberg, Germany
- Institute of Medical Biometry, Heidelberg University, Heidelberg, Germany
- National Pediatric Haemodialysis Centre and Renal Transplant Unit, Temple Street Children’s University Hospital, Dublin, Ireland
- Pediatric Nephrology Unit, Department of Women’s and Children’s Health, Padua University Hospital, Italy
- Division of Pediatric Nephrology, Hacettepe University Faculty of Medicine, Ankara, Türkiye
- Division of Nephrology, Dialysis and Transplant Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
- Department of Pediatric Nephrology, Nottingham University Hospitals, Nottingham, UK
- Department of General Pediatrics, University Children’s Hospital Münster, Münster, Germany
- Department of Nephrology, Kidney Transplantation and Hypertension, The Children's Memorial Health Institute, Warsaw, Poland
- Division of Pediatric Nephrology, University Hamburg-Eppendorf, Hamburg, Germany
- Department of Pediatrics II, University Hospital of Essen, Essen, Germany
- Pediatric Nephrology Unit, Regina Margherita Department, Azienda Ospedaliero-Universitaria Città Della Salute e della Scienza, Torino, Italy
- Department of Pediatric Nephrology, Royal Manchester Children's Hospital, Manchester, UK
- Pediatric Nephrology Unit, Dialysis and Transplantation Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
- Pediatric Nephrology, Children's and Adolescents' Hospital, University Hospital of Cologne, Faculty of Medicine, University of Cologne, Köln, Germany
- Department of Pediatrics, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic
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Xie W, Fan S, Liu R, Yan W, Su C, Zheng K, Wang X, Wang Z. Tacrolimus intra-patient variability measures and its associations with allograft clinical outcomes in kidney transplantation. Transplant Rev (Orlando) 2024; 38:100842. [PMID: 38537484 DOI: 10.1016/j.trre.2024.100842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 03/14/2024] [Accepted: 03/15/2024] [Indexed: 06/16/2024]
Abstract
AIMS Tacrolimus (Tac) is commonly prescribed in solid organ transplantation to prevent immune-mediated damage to the graft. However, its pharmacokinetics show substantial variability between and within patients. Intra-patient variability of tacrolimus (Tac-IPV) has emerged as a novel marker to predict transplant outcomes. Numerous studies report varying associations between Tac-IPV and clinical outcomes, with Tac-IPV measures showing wide discrepancies among these studies. This inconsistency could be a significant factor that influences the various outcomes reported in different studies. Our review comprehensively assesses the relationship between various Tac-IPV measures and their associations with clinical outcomes in transplant patients. METHODS A comprehensive literature search was conducted using the PubMed and Embase databases, covering the period from 2004 to March 31, 2023. The search focused on studies that examined the relationship between Tac-IPV and clinical outcomes in kidney transplantation (KT). The inclusion criteria were specific to studies addressing Tac-IPV, including measures such as standard deviation (SD), coefficient of variation (CV), time-weighted coefficient of variability (CV), mean absolute deviation (MAD), and Tac variability score (TVS). Clinical outcomes included the development of de novo donor-specific antibodies (dnDSA), rejection episodes, graft loss, and graft failure. RESULTS Among the 33 studies that met the inclusion criteria, a notable proportion presented conflicting findings in their assessment of various Tac-IPV measures regarding dnDSA, rejection episodes, graft loss, and graft failure. CONCLUSIONS Most studies have identified a correlation between high Tac-IPV and poor clinical outcomes; however, this relationship is multifactorial. Influencing factors include the metabolic status of KT patients, the timing of Tac-IPV calculations, and the criteria for defining high and low Tac-IPV thresholds, including the size and selection method. CV, MAD, and TWCV are the metrics that are most frequently used to determine Tac-IPV. Additionally, most of the methods for establishing Tac-IPV thresholds typically employ receiver operating characteristic (ROC) curves and median values. It is also notable that studies examining the clinical significance of Tac-IPV often include tacrolimus levels measured six months after kidney transplantation.
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Affiliation(s)
- Wenmin Xie
- Department of Pharmacy, Shanghai Changhai Hospital, Naval Medical University, Shanghai, People's Republic of China; College of life sciences and Biopharmaceuticals, Shenyang Pharmaceutical University, Shenyang, People's Republic of China
| | - Shupan Fan
- Department of Pharmacy, Shanghai Changhai Hospital, Naval Medical University, Shanghai, People's Republic of China; Department of Gastroenterology, Digestive Endoscopy Center, Changhai Hospital, Naval Medical University, Shanghai, People's Republic of China
| | - Ruolin Liu
- Department of Pharmacy, Shanghai Changhai Hospital, Naval Medical University, Shanghai, People's Republic of China; College of life sciences and Biopharmaceuticals, Shenyang Pharmaceutical University, Shenyang, People's Republic of China
| | - Wencheng Yan
- Department of Pharmacy, Shanghai Changhai Hospital, Naval Medical University, Shanghai, People's Republic of China; School of Pharmacy, Bengbu Medical University, Bengbu, People's Republic of China
| | - Chengxin Su
- Department of Pharmacy, Shanghai Changhai Hospital, Naval Medical University, Shanghai, People's Republic of China; College of life sciences and Biopharmaceuticals, Shenyang Pharmaceutical University, Shenyang, People's Republic of China
| | - Kaile Zheng
- Department of Pharmacy, Shanghai Changhai Hospital, Naval Medical University, Shanghai, People's Republic of China; School of Pharmacy, Bengbu Medical University, Bengbu, People's Republic of China
| | - Xuebin Wang
- Department of pharmacy, Shanghai Children's Hospital, School of medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China.
| | - Zhuo Wang
- Department of Pharmacy, Shanghai Changhai Hospital, Naval Medical University, Shanghai, People's Republic of China; College of life sciences and Biopharmaceuticals, Shenyang Pharmaceutical University, Shenyang, People's Republic of China; Department of Gastroenterology, Digestive Endoscopy Center, Changhai Hospital, Naval Medical University, Shanghai, People's Republic of China; School of Pharmacy, Bengbu Medical University, Bengbu, People's Republic of China.
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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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van den Broek DAJ, Meziyerh S, Budde K, Lefaucheur C, Cozzi E, Bertrand D, López del Moral C, Dorling A, Emonds MP, Naesens M, de Vries APJ, the ESOT Working Group Subclinical DSA Monitoring. The Clinical Utility of Post-Transplant Monitoring of Donor-Specific Antibodies in Stable Renal Transplant Recipients: A Consensus Report With Guideline Statements for Clinical Practice. Transpl Int 2023; 36:11321. [PMID: 37560072 PMCID: PMC10408721 DOI: 10.3389/ti.2023.11321] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 06/22/2023] [Indexed: 08/11/2023]
Abstract
Solid phase immunoassays improved the detection and determination of the antigen-specificity of donor-specific antibodies (DSA) to human leukocyte antigens (HLA). The widespread use of SPI in kidney transplantation also introduced new clinical dilemmas, such as whether patients should be monitored for DSA pre- or post-transplantation. Pretransplant screening through SPI has become standard practice and DSA are readily determined in case of suspected rejection. However, DSA monitoring in recipients with stable graft function has not been universally established as standard of care. This may be related to uncertainty regarding the clinical utility of DSA monitoring as a screening tool. This consensus report aims to appraise the clinical utility of DSA monitoring in recipients without overt signs of graft dysfunction, using the Wilson & Junger criteria for assessing the validity of a screening practice. To assess the evidence on DSA monitoring, the European Society for Organ Transplantation (ESOT) convened a dedicated workgroup, comprised of experts in transplantation nephrology and immunology, to review relevant literature. Guidelines and statements were developed during a consensus conference by Delphi methodology that took place in person in November 2022 in Prague. The findings and recommendations of the workgroup on subclinical DSA monitoring are presented in this article.
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Affiliation(s)
- Dennis A. J. van den Broek
- Division of Nephrology, Department of Medicine, Leiden Transplant Center, Leiden University Medical Center, Leiden University, Leiden, Netherlands
| | - Soufian Meziyerh
- Division of Nephrology, Department of Medicine, Leiden Transplant Center, Leiden University Medical Center, Leiden University, Leiden, Netherlands
| | - Klemens Budde
- Department of Nephrology and Medical Intensive Care, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Carmen Lefaucheur
- Paris Translational Research Center for Organ Transplantation, Kidney Transplant Department, Saint Louis Hospital, Université de Paris Cité, Paris, France
| | - Emanuele Cozzi
- Department of Cardiac, Thoracic and Vascular Sciences and Public Health, Transplant Immunology Unit, Padua University Hospital, Padua, Italy
| | - Dominique Bertrand
- Department of Nephrology, Transplantation and Hemodialysis, Rouen University Hospital, Rouen, France
| | - Covadonga López del Moral
- Department of Nephrology and Medical Intensive Care, Charité Universitätsmedizin Berlin, Berlin, Germany
- Valdecilla Biomedical Research Institute (IDIVAL), Santander, Spain
| | - Anthony Dorling
- Department of Inflammation Biology, Centre for Nephrology, Urology and Transplantation, School of Immunology & Microbial Sciences, King’s College London, Guy’s Hospital, London, United Kingdom
| | - Marie-Paule Emonds
- Histocompatibility and Immunogenetics Laboratory (HILA), Belgian Red Cross-Flanders, Mechelen, Belgium
- Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
| | - Maarten Naesens
- Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
| | - Aiko P. J. de Vries
- Division of Nephrology, Department of Medicine, Leiden Transplant Center, Leiden University Medical Center, Leiden University, Leiden, Netherlands
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Betjes MGH, De Weerd A. Lowering maintenance immune suppression in elderly kidney transplant recipients; connecting the immunological and clinical dots. Front Med (Lausanne) 2023; 10:1215167. [PMID: 37502354 PMCID: PMC10368955 DOI: 10.3389/fmed.2023.1215167] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Accepted: 06/09/2023] [Indexed: 07/29/2023] Open
Abstract
The management of long-term immune suppressive medication in kidney transplant recipients is a poorly explored field in the area of transplant medicine. In particular, older recipients are at an increased risk for side effects and have an exponentially increased risk of infection-related death. In contrast, an aged immune system decreases the risk of acute T-cell-mediated rejection in older recipients. Recent advances in alloimmunity research have shown a rapid and substantial decline in polyfunctional, high-risk CD4+ T cells post-transplantation. This lowers the direct alloreactivity responsible for T-cell-mediated rejection, also known as donor-specific hyporesponsiveness. Chronic antibody-mediated rejection (c-aABMR) is the most frequent cause of kidney graft loss in the long term. However, in older adults, c-aABMR as a cause of graft loss is outnumbered by death with a functioning graft. In addition, DSA development and a diagnosis of c-aABMR plateau ~10 years after transplantation, resulting in a very low risk for rejection thereafter. The intensity of immune suppression regimes could likely be reduced accordingly, but trials in this area are scarce. Tacrolimus monotherapy for 1 year after transplantation seems feasible in older kidney transplant recipients with standard immunological risk, showing the expected benefits of fewer infections and better vaccination responses.
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9
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Reininger KA, Onyeaghala G, Anderson-Haag T, Schladt DS, Wu B, Guan W, Dorr CR, Remmel RP, Mannon R, Matas AJ, Oetting WS, Stahler P, Israni AK, Jacobson PA. Higher number of tacrolimus dose adjustments in kidney transplant recipients who are extensive and intermediate CYP3A5 metabolizers. Clin Transplant 2023; 37:e14893. [PMID: 36571802 PMCID: PMC10089949 DOI: 10.1111/ctr.14893] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Accepted: 12/20/2022] [Indexed: 12/27/2022]
Abstract
Kidney transplant recipients carrying the CYP3A5*1 allele have lower tacrolimus troughs, and higher dose requirements compared to those with the CYP3A5*3/*3 genotype. However, data on the effect of CYP3A5 alleles on post-transplant tacrolimus management are lacking. The effect of CYP3A5 metabolism phenotypes on the number of tacrolimus dose adjustments and troughs in the first 6 months post-transplant was evaluated in 78 recipients (64% Caucasians). Time to first therapeutic concentration, percentage of time in therapeutic range (TTR), and estimated glomerular filtration rate (eGFR) were also evaluated. Fifty-five kidney transplant recipients were CYP3A5 poor metabolizers (PM), 17 were intermediate metabolizers (IM), and 6 were extensive metabolizers (EM). Compared to PMs, EMs/IMs had significantly more dose adjustments (6.1 vs. 8.1, p = .015). Overall, 33.82% of trough measurements resulted in a dose change. There was no difference in the number of tacrolimus trough measurements between PMs and EM/IMs. The total daily tacrolimus dose requirements were higher in EMs and IMs compared to PMs (<.001). TTR was ∼50% in the PMs and EMs/IMs groups. CYP3A5 EM/IM metabolizers have more tacrolimus dose changes and higher dose requirements which increases clinical management complexity. Larger studies are needed to assess the cost and benefits of including genotyping data to improve clinical management.
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Affiliation(s)
- Kevin A Reininger
- Department of Pharmacy, Hennepin County Medical Center, Minneapolis, Minnesota, USA
| | - Guillaume Onyeaghala
- Hennepin Healthcare Research Institute, Minneapolis, Minnesota, USA
- Division of Nephrology, Hennepin Healthcare, University of Minnesota, Minneapolis, Minnesota, USA
| | - Teresa Anderson-Haag
- Department of Pharmacy, Hennepin County Medical Center, Minneapolis, Minnesota, USA
| | - David S Schladt
- Hennepin Healthcare Research Institute, Minneapolis, Minnesota, USA
| | - Baolin Wu
- Department of Biostatistics, University of Minnesota, Minneapolis, Minnesota, USA
| | - Weihua Guan
- Department of Biostatistics, University of Minnesota, Minneapolis, Minnesota, USA
| | - Casey R Dorr
- Hennepin Healthcare Research Institute, Minneapolis, Minnesota, USA
- Division of Nephrology, Hennepin Healthcare, University of Minnesota, Minneapolis, Minnesota, USA
| | - Rory P Remmel
- Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota, USA
| | - Roslyn Mannon
- Division of Nephrology, University of Nebraska, Omaha, Nebraska, USA
| | - Arthur J Matas
- Department of Surgery, University of Minnesota, Minneapolis, Minnesota, USA
| | - William S Oetting
- Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota, USA
| | - Paul Stahler
- Division of Surgery, Hennepin Healthcare, Minneapolis, Minnesota, USA
| | - Ajay K Israni
- Division of Nephrology, Hennepin Healthcare, University of Minnesota, Minneapolis, Minnesota, USA
- Department of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota, USA
| | - Pamala A Jacobson
- Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota, USA
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10
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de Weerd AE, Fatly ZA, Boer-Verschragen M, Kal-van Gestel JA, Roelen DL, Dieterich M, Betjes MGH. Tacrolimus Monotherapy is Safe in Immunologically Low-Risk Kidney Transplant Recipients: A Randomized-Controlled Pilot Study. Transpl Int 2022; 35:10839. [PMID: 36353052 PMCID: PMC9637544 DOI: 10.3389/ti.2022.10839] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Accepted: 10/12/2022] [Indexed: 12/02/2022]
Abstract
In this randomized-controlled pilot study, the feasibility and safety of tacrolimus monotherapy in immunologically low-risk kidney transplant recipients was evaluated [NTR4824, www.trialregister.nl]. Low immunological risk was defined as maximal 3 HLA mismatches and the absence of panel reactive antibodies. Six months after transplantation, recipients were randomized if eGFR >30 ml/min, proteinuria <50 mg protein/mmol creatinine, no biopsy-proven rejection after 3 months, and no lymphocyte depleting therapy given. Recipients were randomized to tacrolimus/mycophenolate mofetil (TAC/MMF) or to taper and discontinue MMF at month 9 (TACmono). 79 of the 121 recipients were randomized to either TACmono (n = 38) or TAC/MMF (n = 41). Mean recipient age was 59 years and 59% received a living donor transplant. The median follow-up was 62 months. After randomization, 3 TACmono and 4 TAC/MMF recipients experienced a biopsy-proven rejection. At 5 years follow-up, patient survival was 84% in TACmono versus 76% in TAC/MMF with death-censored graft survival of 97% for both groups and no differences in eGFR and proteinuria. Eleven TACmono recipients had an infectious episode versus 22 TAC/MMF recipients (p < 0.03). Donor-specific anti-HLA antibodies were not detected during follow-up in both groups. Tacrolimus monotherapy in selected immunologically low-risk kidney transplant recipients appears safe and reduces the number of infections.
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Affiliation(s)
- Annelies E. de Weerd
- Department of Internal Medicine, University Medical Center Rotterdam, Erasmus MC Transplant Institute, Rotterdam, Netherlands
| | - Zainab Al Fatly
- Department of Internal Medicine, University Medical Center Rotterdam, Erasmus MC Transplant Institute, Rotterdam, Netherlands
| | - Marieken Boer-Verschragen
- Department of Internal Medicine, University Medical Center Rotterdam, Erasmus MC Transplant Institute, Rotterdam, Netherlands
| | - Judith A. Kal-van Gestel
- Department of Internal Medicine, University Medical Center Rotterdam, Erasmus MC Transplant Institute, Rotterdam, Netherlands
| | - Dave L. Roelen
- Department of Immunology, HLA Laboratory, Leiden University Medical Center, Leiden, Netherlands
| | - Marjolein Dieterich
- Department of Internal Medicine, University Medical Center Rotterdam, Erasmus MC Transplant Institute, Rotterdam, Netherlands
| | - Michiel G. H. Betjes
- Department of Internal Medicine, University Medical Center Rotterdam, Erasmus MC Transplant Institute, Rotterdam, Netherlands
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11
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Baghai Arassi M, Gauche L, Schmidt J, Höcker B, Rieger S, Süsal C, Tönshoff B, Fichtner A. Association of intraindividual tacrolimus variability with de novo donor-specific HLA antibody development and allograft rejection in pediatric kidney transplant recipients with low immunological risk. Pediatr Nephrol 2022; 37:2503-2514. [PMID: 35166920 PMCID: PMC9395307 DOI: 10.1007/s00467-022-05426-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 11/24/2021] [Accepted: 12/13/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND Tacrolimus (Tac) intraindividual variability (TacIPV) in pediatric kidney transplant patients is only poorly understood. We investigated the impact of TacIPV on de novo donor-specific HLA antibodies (dnDSA) development and allograft rejection in Caucasian pediatric recipients of a living or deceased donor kidney with low immunological risk. METHODS This was a single-center retrospective study including 48 pediatric kidney transplant recipients. TacIPV was calculated based on coefficient of variation (CV%) 6-12 months posttransplant. TacIPV cutoff was set at the median (25%). Outcome parameters were dnDSA development and rejection episodes. RESULTS In total, 566 Tac levels were measured with median 11.0 (6.0-17.0) measurements per patient. The cutoff of 25% corresponded to the median CV% in our study cohort (25%, IQR 18-35%) and was comparable to cutoffs determined by receiver operating characteristic (ROC) curve analysis. High TacIPV was associated with higher risk of dnDSA development (HR 3.4, 95% CI 1.0-11.1, P = 0.047; Kaplan-Meier analysis P = 0.018) and any kind of rejection episodes (HR 4.1, 95% CI 1.1-14.8, P = 0.033; Kaplan-Meier analysis P = 0.010). There was a clear trend towards higher TacIPV below the age of 6 years. TacIPV (CV%) was stable over time. A TacIPV (CV%) cutoff of 30% or IPV quantification by mean absolute deviation (MAD) showed comparable results. CONCLUSIONS High TacIPV is associated with an increased risk of dnDSA development and rejection episodes > year 1 posttransplant even in patients with low immunological risk profile. Therefore, in patients with high TacIPV, potential causes should be addressed, and if not resolved, changes in immunosuppressive therapy should be considered. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Affiliation(s)
- Maral Baghai Arassi
- Department of Pediatrics I, University Children's Hospital Heidelberg, Heidelberg, Germany. .,Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
| | - Laura Gauche
- Department of Pediatrics I, University Children’s Hospital Heidelberg, Heidelberg, Germany
| | - Jeremy Schmidt
- Department of Pediatrics I, University Children’s Hospital Heidelberg, Heidelberg, Germany
| | - Britta Höcker
- Department of Pediatrics I, University Children’s Hospital Heidelberg, Heidelberg, Germany
| | - Susanne Rieger
- Department of Pediatrics I, University Children’s Hospital Heidelberg, Heidelberg, Germany
| | - Caner Süsal
- Institute of Immunology, Transplantation Immunology, University Hospital Heidelberg, Heidelberg, Germany
| | - Burkhard Tönshoff
- Department of Pediatrics I, University Children’s Hospital Heidelberg, Heidelberg, Germany
| | - Alexander Fichtner
- Department of Pediatrics I, University Children’s Hospital Heidelberg, Heidelberg, Germany
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12
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Bunthof KLW, Al-Hassany L, Nakshbandi G, Hesselink DA, van Schaik RHN, Ten Dam MAGJ, Baas MC, Hilbrands LB, van Gelder T. A randomized crossover study comparing different tacrolimus formulations to reduce intrapatient variability in tacrolimus exposure in kidney transplant recipients. Clin Transl Sci 2021; 15:930-941. [PMID: 34905302 PMCID: PMC9010272 DOI: 10.1111/cts.13206] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 10/23/2021] [Accepted: 11/17/2021] [Indexed: 12/05/2022] Open
Abstract
A high intrapatient variability (IPV) in tacrolimus exposure is a risk factor for poor long‐term outcomes after kidney transplantation. The main objective of this trial was to investigate whether tacrolimus IPV decreases after switching patients from immediate‐release (IR)‐tacrolimus to either extended‐release (ER)‐tacrolimus or LifeCyclePharma (LCP)‐tacrolimus. In this randomized, prospective, open‐label, cross‐over trial, adult kidney transplant recipients on a stable immunosuppressive regimen, including IR‐tacrolimus, were randomized for conversion to ER‐tacrolimus or LCP‐tacrolimus, and for the order in which IR‐tacrolimus and the once‐daily formulations were taken. Patients were followed 6 months for each formulation, with monthly tacrolimus predose concentration assessments to calculate the IPV. The IPV was defined as the coefficient of variation (%) of dose corrected predose concentrations. Ninety‐two patients were included for analysis of the primary outcome. No significant differences between the IPV of IR‐tacrolimus (16.6%) and the combined once‐daily formulations (18.3%) were observed (% difference +1.7%, 95% confidence interval [CI] −1.1% to ‒4.5%, p = 0.24). The IPV of LCP‐tacrolimus (20.1%) was not significantly different from the IPV of ER‐tacrolimus (16.5%, % difference +3.6%, 95% CI −0.1% to 7.3%, p = 0.06). In conclusion, the IPV did not decrease after switching from IR‐tacrolimus to either ER‐tacrolimus or LCP‐tacrolimus. These results provide no arguments to switch kidney transplant recipients from twice‐daily (IR) tacrolimus formulations to once‐daily (modified‐release) tacrolimus formulations when the aim is to lower the IPV.
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Affiliation(s)
- Kim L W Bunthof
- Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands.,Department of Internal Medicine, Bravis Hospital, Roosendaal, The Netherlands
| | - Linda Al-Hassany
- Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Gizal Nakshbandi
- Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Dennis A Hesselink
- Internal Medicine, Division of Nephrology and Transplantation, Erasmus University Medical Center, Rotterdam, The Netherlands.,Erasmus University Medical Center, Erasmus MC Transplant Institute, Rotterdam, The Netherlands
| | - Ron H N van Schaik
- Clinical Chemistry, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Marc A G J Ten Dam
- Department of Internal Medicine, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands
| | - Marije C Baas
- Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Luuk B Hilbrands
- Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Teun van Gelder
- Internal Medicine, Division of Nephrology and Transplantation, Erasmus University Medical Center, Rotterdam, The Netherlands.,Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands
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13
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Stefanović N, Veličković-Radovanović R, Danković K, Pavlović I, Catić-Đorđević A, Bašić J, Despotović M, Jevtović-Stoimenov T, Mitić B, Cvetković T. Effect of the Interrelation between CYP3A5 Genotype, Concentration/Dose Ratio and Intrapatient Variability of Tacrolimus on Kidney Graft Function: Monte Carlo Simulation Approach. Pharmaceutics 2021; 13:1970. [PMID: 34834385 PMCID: PMC8622919 DOI: 10.3390/pharmaceutics13111970] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 11/02/2021] [Accepted: 11/04/2021] [Indexed: 12/04/2022] Open
Abstract
Background: Tacrolimus (Tac) is characterized by large between- and within-patient (IPV) variability in pharmacokinetics and exposure. Aim: This study aimed to assess and validate the effect of Tac IPV and trough concentration-to-dose ratio (C0/D) over 6-12 months on reduced estimated glomerular filtration rate (eGFR) values in the late period after kidney transplantation (Tx), applying Monte Carlo (MC) simulation. Methods: The previously published linear regression was the basis for MC simulation, performed to determine how variations in significant predictors affect the distribution of eGFR from 13 to 36 months post-transplantation. The input C0/D values were derived from CYP3A5 genotype subgroups. Results: Patients characterized by high Tac IPV and low mean C0/D over 6-12 months could have been at greater risk of lower eGFR values in a three-year period following Tx compared to the other patient groups. This effect was more pronounced in patients with a lower eGFR at the 6th month and a history of acute rejection. The proven contribution of CYP3A5 expresser genotype to low C0/D values may suggest its indirect effect on long-term graft function. Conclusion: The findings indicate that simultaneous assessment of Tac IPV, C0/D, and CYP3A5 genotype may identify patients at risk of deterioration of graft function in the long-term post-transplantation period.
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Affiliation(s)
- Nikola Stefanović
- Department of Pharmacy, Faculty of Medicine, University of Nis, 18000 Nis, Serbia;
| | - Radmila Veličković-Radovanović
- Department of Pharmacology with Toxicology, Faculty of Medicine, University of Nis, 18000 Nis, Serbia;
- Clinic of Nephrology, University Clinical Center Nis, 18000 Nis, Serbia;
| | | | - Ivan Pavlović
- Faculty of Mechanical Engineering, University of Nis, 18000 Nis, Serbia;
| | | | - Jelena Bašić
- Department of Biochemistry, Faculty of Medicine, University of Nis, 18000 Nis, Serbia; (J.B.); (M.D.); (T.J.-S.); (T.C.)
| | - Milena Despotović
- Department of Biochemistry, Faculty of Medicine, University of Nis, 18000 Nis, Serbia; (J.B.); (M.D.); (T.J.-S.); (T.C.)
| | - Tatjana Jevtović-Stoimenov
- Department of Biochemistry, Faculty of Medicine, University of Nis, 18000 Nis, Serbia; (J.B.); (M.D.); (T.J.-S.); (T.C.)
| | - Branka Mitić
- Clinic of Nephrology, University Clinical Center Nis, 18000 Nis, Serbia;
- Department of Internal Medicine, Faculty of Medicine, University of Nis, 18000 Nis, Serbia
| | - Tatjana Cvetković
- Department of Biochemistry, Faculty of Medicine, University of Nis, 18000 Nis, Serbia; (J.B.); (M.D.); (T.J.-S.); (T.C.)
- Center for Clinical and Medical Biochemistry, University Clinical Center Nis, 18000 Nis, Serbia
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14
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Larpparisuth N, Pongnatcha T, Panprom P, Promraj R, Premasathian N, Vongwiwatana A. High Intrapatient Variability in Tacrolimus Exposure Calculated Over a Long Period Is Associated With De Novo Donor-Specific Antibody Development and/or Late Rejection in Thai Kidney Transplant Patients Receiving Concomitant CYP3A4/5 Inhibitors. Ther Drug Monit 2021; 43:624-629. [PMID: 33278239 DOI: 10.1097/ftd.0000000000000850] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Accepted: 08/16/2020] [Indexed: 01/08/2023]
Abstract
BACKGROUND High intrapatient variability in tacrolimus trough levels (Tac IPV) is associated with poor allograft outcomes. Tac IPV was previously calculated using trough levels 6-12 months after kidney transplantation (KT). Data on the accuracy of Tac IPV calculation over a longer period, the association between high Tac IPV and donor-specific antibody (DSA) development after KT in Asian patients, and the role of IPV in patients receiving concomitant cytochrome P450 (CYP)3A4/5 inhibitors (CYPinh) are limited. METHODS A retrospective review of patients who underwent KT at our center in 2005-2015, and who received Tac with mycophenolate during the first 2 years after KT was performed. IPV was calculated using Tac levels adjusted by dosage. DSA was monitored annually after KT using a Luminex microbead assay. RESULTS In total, 236 patients were enrolled. CYPinh were prescribed to 189 patients (80.1%): 145 (61.4%), 31 (13.1%), and 13 (5.5%) received diltiazem, fluconazole, and ketoconazole, respectively. Mean IPV calculated from adjusted Tac levels for 6-12 months (IPV6-12) and 6-24 months (IPV6-24) after KT were 20.64% ± 11.68% and 23.53% ± 10.39%, respectively. Twenty-six patients (11%) showed late rejection and/or DSA occurrence, and had significantly higher IPV6-24 (29.42% ± 13.78%) than others (22.77% ± 9.64%; P = 0.02). There was no difference in IPV6-12 (24.31% ± 14.98% versus 20.17% ± 10.90%; P = 0.18). IPV6-12 and IPV6-24 were comparable in patients who did and did not receive CYPinh. When using mean IPV6-24 as a cutoff, patients with higher IPV6-24 had a higher probability of developing DSA and/or late rejection (P = 0.048). CONCLUSIONS Tac IPV6-24 was higher and more significantly associated with DSA development and/or late rejection than Tac IPV6-12, independent of Tac trough level. This is the first study to demonstrate the impact of high IPV on DSA development in Asian patients, and that Tac IPV is comparable between patients with and without CYPinh.
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Affiliation(s)
- Nuttasith Larpparisuth
- Division of Nephrology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University
| | - Tanapon Pongnatcha
- Division of Nephrology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University
| | - Pera Panprom
- Department of Nursing Siriraj Hospital, Faculty of Medicine Siriraj Hospital, Mahidol University; and
| | - Ratchawat Promraj
- Ambulatory Pharmaceutical Care Unit, Pharmacy Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Nalinee Premasathian
- Division of Nephrology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University
| | - Attapong Vongwiwatana
- Division of Nephrology, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University
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15
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Betjes MGH, Kho MML, Litjens NHR, de Weerd AE, Roodnat JI. Alemtuzumab as Second-Line Treatment for Late Antibody-Mediated Rejection of Transplanted Kidneys. Transplant Proc 2021; 53:2206-2211. [PMID: 34376313 DOI: 10.1016/j.transproceed.2021.07.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 06/30/2021] [Accepted: 07/19/2021] [Indexed: 01/10/2023]
Abstract
Whether the anti-CD52 monoclonal antibody alemtuzumab can be an effective treatment option for late antibody-mediated rejection (ABMR) is not known. In a single-center pilot study, 12 patients with late ABMR were given 30 mg subcutaneous alemtuzumab.Median time from transplantation to biopsy was 22 months with 10 of 12 recipients fulfilling criteria for the histologic diagnosis chronic-active ABMR. The estimated glomerular filtration rate (eGFR) loss before diagnosis was 1.2 mL/min/mo with graft loss (eGFR <15 mL/min) expected to occur within 2 years in 11 of 12 cases. All recipients showed no or an inadequate response to initial treatment with steroids and intravenous immunoglobulin. eGFR at time of alemtuzumab administration was 35 mL/min/1.73 m2 (IQR, 30-42) and stabilized or improved in 10 of 12 recipients within 12 months. Proteinuria was stable in the year after alemtuzumab. At 3-year follow-up, the death-censored graft survival was 68% (uncensored graft survival was 58%). Five cases of 10 cases that could be evaluated at 3-year follow-up had stable eGFR (on average 44 mL/min at 12 months and 42 mL/min at 36 months). Alemtuzumab was generally well tolerated and only 2 cases of opportunistic infections were noted. One case of symptomatic parvovirus B infection and 1 case of BK viral infection occurred, which both cleared at follow-up. In conclusion, alemtuzumab may be of value as a second-line treatment for late ABMR with rapid loss of eGFR.
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Affiliation(s)
- Michiel G H Betjes
- Nephrology and Transplantation, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
| | - Marcia M L Kho
- Nephrology and Transplantation, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Nicolle H R Litjens
- Nephrology and Transplantation, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Annelies E de Weerd
- Nephrology and Transplantation, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Joke I Roodnat
- Nephrology and Transplantation, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
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16
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Clinical Implications of Tacrolimus Time in Therapeutic Range and Intrapatient Variability in Urban Renal Transplant Recipients Undergoing Early Corticosteroid Withdrawal. Transplant Direct 2021; 7:e698. [PMID: 34036168 PMCID: PMC8133158 DOI: 10.1097/txd.0000000000001155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Accepted: 03/02/2021] [Indexed: 11/25/2022] Open
Abstract
Tacrolimus demonstrates wide intrapatient and interpatient variability requiring therapeutic drug monitoring. The utility of tacrolimus time in therapeutic range (TTR) after renal transplantation (RT) under an early corticosteroid withdrawal (ECSWD) protocol is unknown. The purpose of this study is to assess the impact of tacrolimus TTR in an ECSWD RT population. Materials A retrospective analysis of adult RT recipients maintained on tacrolimus was conducted. Patients were excluded if they were on nonstandard protocol immunosuppression agents <12 months post-RT. Tacrolimus TTR was calculated using the Rosendaal method. Patients were divided into high (TTR-H) and low (TTR-L) TTR groups based on cohort median. The primary outcome was to compare the incidence of acute rejection 12 months post-RT. Secondary outcomes included comparing rejection subtypes, incidence of donor-specific antibody (DSA) and de novo DSA (dnDSA), risk factors for acute rejection and dnDSA development, and allograft function (serum creatinine and estimated glomerular filtration rate). Results A total of 193 patients were analyzed (TTR-H = 98 and TTR-L = 95). There was no difference in the incidence of acute rejection (TTR-H 20.4% versus TTR-L 20.0%; P = 0.944). Positive DSA posttransplant (odds ratio [OR], 3.62; 95% confidence interval [CI], 1.41-9.26; P = 0.007) was associated with a higher acute rejection at 12 months posttransplant. Mycophenolate dose reduction (OR, 2.82; 95% CI, 1.13-6.97; P = 0.025) and acute rejection (OR, 2.99; 95% CI, 1.09-8.18; P = 0.032) were associated with dnDSA formation. No difference in serum creatinine or estimated glomerular filtration rate was observed (P > 0.05). Conclusions Tacrolimus TTR was not significantly different with regards to acute rejection in an ECSWD population. Future studies are still needed to determine tacrolimus TTR thresholds post-RT and identify populations that may benefit from this intrapatient variability monitoring parameter.
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17
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BK Polyomavirus Nephropathy in Kidney Transplantation: Balancing Rejection and Infection. Viruses 2021; 13:v13030487. [PMID: 33809472 PMCID: PMC7998398 DOI: 10.3390/v13030487] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 03/12/2021] [Accepted: 03/14/2021] [Indexed: 12/16/2022] Open
Abstract
BK polyomavirus nephropathy (BKVN) and allograft rejection are two closely-associated diseases on opposite ends of the immune scale in kidney transplant recipients. The principle of balancing the immune system remains the mainstay of therapeutic strategy. While patient outcomes can be improved through screening, risk factors identification, and rapid reduction of immunosuppressants, a lack of standard curative therapy is the primary concern during clinical practice. Additionally, difficulty in pathological differential diagnosis and clinicopathology’s dissociation pose problems for a definite diagnosis. This article discusses the delicate evaluation needed to optimize immunosuppression and reviews recent advances in molecular diagnosis and immunological therapy for BKVN patients. New biomarkers for BKVN diagnosis are under development. For example, measurement of virus-specific T cell level may play a role in steering immunosuppressants. The development of cellular therapy may provide prevention, even a cure, for BKVN, a complex post-transplant complication.
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18
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Betjes MGH, Sablik KA, Litjens NHR, Otten HG, de Weerd AE. ARHGDIB and AT1R autoantibodies are differentially related to the development and presence of chronic antibody-mediated rejection and fibrosis in kidney allografts. Hum Immunol 2021; 82:89-96. [PMID: 33358038 DOI: 10.1016/j.humimm.2020.12.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 12/03/2020] [Accepted: 12/05/2020] [Indexed: 12/22/2022]
Abstract
The role of non-HLA autoantibodies in chronic-active antibody-mediated rejection (c-aABMR) of kidney transplants is largely unknown. In this study, the presence and clinical relevance of non-HLA autoantibodies using a recently developed multiplex Luminex-based assay were investigated. Patients with a kidney allograft biopsy at least 6 months after transplantation with a diagnosis of c-aABMR (n = 36) or no rejection (n = 21) were included. Pre-transplantation sera and sera at time of biopsy were tested for the presence of 14 relevant autoantibodies. A significantly higher signal for autoantibodies against Rho GDP-dissociation inhibitor 2 (ARHGDIB) was detected in recipients with c-aABMR as compared to recipients with no rejection. However, ARHGDIB autoantibodies did not associate with graft survival. Levels of autoantibodies against angiotensin II type 1-receptor (AT1R) and peroxisomal trans-2-enoyl-CoA reductase (PECR) were increased in recipients with interstitial fibrosis in their kidney biopsy. Only the signal for AT1R autoantibody showed a linear relationship with the degree of interstitial fibrosis and was associated with graft survival. In conclusion, anti-ARHGDIB autoantibodies are increased when c-aABMR is diagnosed but are not associated with graft survival, while higher levels of AT1R autoantibody are specifically associated with the presence of interstitial fibrosis and graft survival.
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Affiliation(s)
- Michiel G H Betjes
- Department of Internal Medicine, Section Nephrology and Transplantation, Erasmus MC, University Medical Center, Rotterdam, Rotterdam, the Netherlands.
| | - Kasia A Sablik
- Department of Internal Medicine, Section Nephrology and Transplantation, Erasmus MC, University Medical Center, Rotterdam, Rotterdam, the Netherlands
| | - Nicolle H R Litjens
- Department of Internal Medicine, Section Nephrology and Transplantation, Erasmus MC, University Medical Center, Rotterdam, Rotterdam, the Netherlands
| | - Henny G Otten
- Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Annelies E de Weerd
- Department of Internal Medicine, Section Nephrology and Transplantation, Erasmus MC, University Medical Center, Rotterdam, Rotterdam, the Netherlands
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19
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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: 37] [Impact Index Per Article: 7.4] [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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20
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Stefanović NZ, Veličković-Radovanović RM, Danković KS, Mitić BP, Paunović GJ, Cvetković MB, Cvetković TP. Combined Effect of Inter- and Intrapatient Variability in Tacrolimus Exposure on Graft Impairment Within a 3-Year Period Following Kidney Transplantation: A Single-Center Experience. Eur J Drug Metab Pharmacokinet 2020; 45:749-760. [PMID: 32886348 DOI: 10.1007/s13318-020-00644-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND AND OBJECTIVE Tacrolimus is a cornerstone of the most immunosuppressive protocols after kidney transplantation, but its use is complicated by notable interpatient and intrapatient variability (IPV). The goal of this study was to evaluate whether or not tacrolimus IPV, or average dose-adjusted trough concentration (C0/D), during 6-12 months post-transplantation might have contributed to graft function decline in a 3-year period following kidney transplantation. After primary evaluation of individual effects of tacrolimus IPV and C0/D, the study aimed to estimate the combined effect of tacrolimus IPV and C0/D on composite endpoint (consisting of graft failure, chronic allograft dysfunction, chronic rejection, and doubling of serum creatinine concentration) in the period between 13 and 36 months after kidney transplantation. In addition, the goal was to analyze the impact of genetics on interpatient variability in tacrolimus exposure in the early and late post-transplantation periods. METHODS The study enrolled 104 Caucasian patients and included 2541 patient examinations up to 36 months after kidney transplantation. All patients were genotyped on CYP3A5 6986A>G and ABCB1 3435C>T gene polymorphism. Patients were divided into groups based on the tacrolimus IPV tertiles and the median value of average C0/D during 6-12 months post-transplantation. RESULTS The results showed a more pronounced decline in estimated glomerular filtration rate values within the high IPV tertile group (p = 0.018), as well as within the low C0/D group (p = 0.013) in a 3-year period after kidney transplantation. The carriers of CYP3A5*1/*3 genotype had lower C0/D compared to the CYP3A5*3/*3 carriers during the entire study period, while the results for ABCB1 were inconsistent when considering tacrolimus C0/D. Patients with high IPV/low C0/D had significantly reduced graft survival compared to the other tacrolimus IPV/C0/D combination groups (i.e., high IPV/high C0/D, low IPV/low C0/D, low IPV/high C0/D) with the hazard ratio of 3.14 in Cox analysis for reaching the composite endpoint. CONCLUSION The findings of this study suggest that combined assessment of tacrolimus IPV and tacrolimus C0/D may categorize patients towards risk of graft deterioration in the long-term post-transplantation period.
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Affiliation(s)
- Nikola Z Stefanović
- Department of Pharmacy, Faculty of Medicine, University of Nis, Dr Zorana Djindjica 81 Blvd., 18000, Nis, Serbia.
| | - Radmila M Veličković-Radovanović
- Department of Pharmacology With Toxicology, Faculty of Medicine, University of Nis, Dr Zorana Djindjica 81 Blvd., , 18000, Nis, Serbia
- Clinic of Nephrology, Clinical Center Nis, Dr Zorana Djindjica 48 Blvd., 18000, Nis, Serbia
| | - Katarina S Danković
- Faculty of Medicine, University of Nis, Dr Zorana Djindjica 81 Blvd., 18000, Nis, Serbia
| | - Branka P Mitić
- Clinic of Nephrology, Clinical Center Nis, Dr Zorana Djindjica 48 Blvd., 18000, Nis, Serbia
- Department of Internal Medicine, Faculty of Medicine, University of Nis, Dr Zorana Djindjica 81 Blvd., 18000, Nis, Serbia
| | - Goran J Paunović
- Clinic of Nephrology, Clinical Center Nis, Dr Zorana Djindjica 48 Blvd., 18000, Nis, Serbia
| | - Mina B Cvetković
- Clinic of Nephrology, Clinical Center Nis, Dr Zorana Djindjica 48 Blvd., 18000, Nis, Serbia
- Faculty of Medicine, University of Nis, Dr Zorana Djindjica 81 Blvd., 18000, Nis, Serbia
| | - Tatjana P Cvetković
- Clinic of Nephrology, Clinical Center Nis, Dr Zorana Djindjica 48 Blvd., 18000, Nis, Serbia
- Department of Biochemistry, Faculty of Medicine, University of Nis, Dr Zorana Djindjica 81 Blvd., 18000, Nis, Serbia
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21
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Gonzales HM, McGillicuddy JW, Rohan V, Chandler JL, Nadig SN, Dubay DA, Taber DJ. A comprehensive review of the impact of tacrolimus intrapatient variability on clinical outcomes in kidney transplantation. Am J Transplant 2020; 20:1969-1983. [PMID: 32406604 PMCID: PMC11140479 DOI: 10.1111/ajt.16002] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 04/19/2020] [Accepted: 04/19/2020] [Indexed: 01/25/2023]
Abstract
Tacrolimus (Tac) is widely used to prevent rejection and graft loss in solid organ transplantation. A limiting characteristic of Tac is the high intra and interpatient variability associated with its use. Routine therapeutic drug monitoring (TDM) is necessary to facilitate Tac management and to avoid undesirable clinical outcomes. However, whole blood trough concentrations commonly utilized in TDM are not strong predictors of the detrimental clinical outcomes of interest. Recently, researchers have focused on Tac intrapatient variability (Tac IPV) as a novel marker to better assess patient risk. Higher Tac IPV has been associated with a number of mechanisms leading to shortened graft survival. Medication nonadherence (MNA) is considered to be the primary determinant of high Tac IPV and perhaps the most modifiable risk factor. An understanding of the methodology behind Tac IPV is imperative to its recognition as an important prognostic measure and integration into clinical practice. Therapeutic interventions targeting MNA and reducing Tac IPV are crucial to improving long-term graft survival.
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Affiliation(s)
- Haley M. Gonzales
- Department of Surgery, Medical University of South Carolina, Charleston, SC
| | | | - Vinayak Rohan
- Department of Surgery, Medical University of South Carolina, Charleston, SC
| | - Jessica L. Chandler
- Department of Nursing Operating, Medical University of South Carolina, Charleston, SC
| | - Satish N. Nadig
- Department of Surgery, Medical University of South Carolina, Charleston, SC
| | - Derek A. Dubay
- Department of Surgery, Medical University of South Carolina, Charleston, SC
| | - David J. Taber
- Department of Surgery, Medical University of South Carolina, Charleston, SC
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22
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Leino AD, Pai MP. Maintenance Immunosuppression in Solid Organ Transplantation: Integrating Novel Pharmacodynamic Biomarkers to Inform Calcineurin Inhibitor Dose Selection. Clin Pharmacokinet 2020; 59:1317-1334. [PMID: 32720300 DOI: 10.1007/s40262-020-00923-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Calcineurin inhibitors, the primary immunosuppressive therapy used to prevent alloreactivity of transplanted organs, have a narrow therapeutic index. Currently, treatment is individualized based on clinical assessment of the risk of rejection or toxicity guided by trough concentration monitoring. Advances in immune monitoring have identified potential markers that may have value in understanding calcineurin inhibitor pharmacodynamics. Integration of these markers has the potential to complement therapeutic drug monitoring. Existing pharmacokinetic-pharmacodynamic (PK-PD) data is largely limited to correlation between the biomarker and trough concentrations at single time points. Immune related gene expression currently has the most evidence supporting PK-PD integration. Novel biomarker-based approaches to pharmacodynamic monitoring including development of enhanced PK-PD models are proposed to realize the full clinical benefit.
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Affiliation(s)
- Abbie D Leino
- Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, 428 Church Street, Rm 3569, Ann Arbor, MI, 48109, USA
| | - Manjunath P Pai
- Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, 428 Church Street, Rm 3569, Ann Arbor, MI, 48109, USA.
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23
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Impacts of High Intra- and Inter-Individual Variability in Tacrolimus Pharmacokinetics and Fast Tacrolimus Metabolism on Outcomes of Solid Organ Transplant Recipients. J Clin Med 2020; 9:jcm9072193. [PMID: 32664531 PMCID: PMC7408675 DOI: 10.3390/jcm9072193] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Accepted: 07/09/2020] [Indexed: 12/14/2022] Open
Abstract
Tacrolimus is a first-line calcineurin inhibitor (CNI) and an integral part of the immunosuppressive strategy in solid organ transplantation. Being a dose-critical drug, tacrolimus has a narrow therapeutic index that necessitates periodic monitoring to maintain the drug’s efficacy and reduce the consequences of overexposure. Tacrolimus is characterized by substantial intra- and inter-individual pharmacokinetic variability. At steady state, the tacrolimus blood concentration to daily dose ratio (C/D ratio) has been described as a surrogate for the estimation of the individual metabolism rate, where a low C/D ratio reflects a higher rate of metabolism. Fast tacrolimus metabolism (low C/D ratio) is associated with the risk of poor outcomes after transplantation, including reduced allograft function and survival, higher allograft rejection, CNI nephrotoxicity, a faster decline in kidney function, reduced death-censored graft survival (DCGS), post-transplant lymphoproliferative disorders, dyslipidemia, hypertension, and cardiovascular events. In this article, we discuss the potential role of the C/D ratio in a noninvasive monitoring strategy for identifying patients at risk for potential adverse events post-transplant.
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24
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Park JB. Future direction of immunosuppressive treatment in organ transplantation. JOURNAL OF THE KOREAN MEDICAL ASSOCIATION 2020. [DOI: 10.5124/jkma.2020.63.5.259] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Since the first success of kidney transplantation in 1954, significant advances have been achieved in the field of organ transplantation. It was possible with the introduction of immunosuppressive drugs belonging to the class of calcineurin inhibitors (CNIs) such as cyclosporine and tacrolimus, the advances in surgical techniques and perioperative management, the monitoring and management infections, and the highly sensitive and specific antibody detection techniques. Despite recent progress, we currently encounter the limitation of better long-term transplant outcomes mainly because of paradoxical CNI toxicity and failure to control antibody or antibody-mediated rejections. The future direction of immunosuppression can be continued by optimizing immunosuppressive regimens with currently available immunosuppressants for better control of antibodies while avoiding CNI toxicity and by using biological therapeutics such as costimulation blockade agents that provide effective control of antibodies along with a reduction in usage or avoidance of CNIs and may develop as new immunosuppressants in the near future. Moreover, a tolerance induction through transplantation of donor hematopoietic stem cells or an infusion of regulatory cells using various sources of immune cells can also be a promising strategy as it can fundamentally escape from the complications of immunosuppressants. Over and above, it is important to note that the results of clinically applicable immunosuppressants from research in the non-human primate xenotransplantation model at the forefront of the future development of immunosuppressants can be a good opportunity to selectively apply to allo-transplants. No immunosuppressants can be risk-free, and therefore, all new immunosuppressants should be evaluated under the considerations for the risk/benefit ratio in various clinical conditions.
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25
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Mendoza Rojas A, Hesselink DA, van Besouw NM, Baan CC, van Gelder T. Impact of low tacrolimus exposure and high tacrolimus intra-patient variability on the development of de novo anti-HLA donor-specific antibodies in kidney transplant recipients. Expert Rev Clin Immunol 2019; 15:1323-1331. [PMID: 31721605 DOI: 10.1080/1744666x.2020.1693263] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Introduction: De novo donor-specific antibodies (dnDSA) directed against HLA are a major contributing factor to the chronic deterioration of renal allograft function. Several factors, including the degree of HLA matching, younger recipient age, and past sensitization events have been shown to increase the risk for the development of dnDSA. The development of dnDSA is also strongly associated with modifications in the immunosuppressive regimen, non-adherence, and under-immunosuppression.Areas covered: Tacrolimus is widely used after solid organ transplantation (SOT) and in recent years, both a high intra-patient variability in tacrolimus exposure and low tacrolimus exposure have been found to be associated with a higher risk of dnDSA development in kidney transplant recipients. This article provides an overview of current findings published in the recent 5 years regarding the relationship between tacrolimus exposure and variation therein and the development of dnDSA.Expert opinion: In this review, we describe how combining data on tacrolimus intra-patient variability and mean pre-dose concentration may be an effective tool to identify kidney transplant recipients who are at higher risk of developing dnDSA.
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Affiliation(s)
- Aleixandra Mendoza Rojas
- Department of Internal Medicine, Nephrology & Transplantation, Erasmus MC, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Dennis A Hesselink
- Department of Internal Medicine, Nephrology & Transplantation, Erasmus MC, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Nicole M van Besouw
- Department of Internal Medicine, Nephrology & Transplantation, Erasmus MC, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Carla C Baan
- Department of Internal Medicine, Nephrology & Transplantation, Erasmus MC, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Teun van Gelder
- Department of Internal Medicine, Nephrology & Transplantation, Erasmus MC, Erasmus University Medical Center, Rotterdam, the Netherlands.,Department of Hospital Pharmacy, Clinical Pharmacology Unit, Erasmus MC, Erasmus University Medical Center, Rotterdam, the Netherlands
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26
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Süsal C, Döhler B. Late intra-patient tacrolimus trough level variability as a major problem in kidney transplantation: A Collaborative Transplant Study Report. Am J Transplant 2019; 19:2805-2813. [PMID: 30859672 DOI: 10.1111/ajt.15346] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Revised: 02/26/2019] [Accepted: 03/07/2019] [Indexed: 01/25/2023]
Abstract
Intra-patient variability (IPV) of tacrolimus trough level has been associated with poor outcome after kidney transplantation. These findings were derived from single-center analyses and restricted mainly to measurements early after transplantation. We analyzed in a multicenter effort whether high IPV of tacrolimus levels at posttransplant years 1, 2, and 3 was associated with impaired clinical outcome. More than 6600 patients who received a deceased donor kidney transplant during 2000-2014 and had a functioning graft for >3 years were studied. Graft survival was significantly impaired with increasing IPV (P < 0.001). As compared to patients with a low IPV of <30%, the risk of graft loss during years 4-6 increased 32% in patients with an IPV of 30% to 44% and 66% in patients with an IPV of ≥45% (P = 0.002 and P < 0.001). About one-third of patients showed an IPV of ≥30% with substantially impaired outcome. Even in patients with good outcome during the first 3 posttransplant years, a high IPV was associated with inferior graft survival. Our data indicate that a fluctuating tacrolimus trough level at years 1, 2, and 3 posttransplant is a major problem in kidney transplantation.
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Affiliation(s)
- Caner Süsal
- Institute of Immunology, Heidelberg University, Heidelberg, Germany
| | - Bernd Döhler
- Institute of Immunology, Heidelberg University, Heidelberg, Germany
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27
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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: 83] [Impact Index Per Article: 13.8] [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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28
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Largeau B, Guellec CBL, Longuet H, Lesne P, Bouvarel A, Préteseille L, Marquet P, Halimi JM, Büchler M, Gatault P, Noble J. Comparison of Tacrolimus Starting Doses Based on CYP3A5 Phenotype or Genotype in Kidney Transplant Recipients. Prog Transplant 2019; 29:300-308. [PMID: 31514576 DOI: 10.1177/1526924819873905] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Selection of expected phenotypes (ie, expressers/non-expressers) is currently used in CYP3A5*3 genotype-based tacrolimus dosing. The authors assessed whether a dosing regimen based on the 3 CYP3A5 genotypes may reduce the occurrence of inadequate exposure. METHODS Tacrolimus whole blood trough levels (C 0) were retrieved from a retrospective cohort of 100 kidney transplant recipients treated with a starting dose of 0.15 (non-expressers) or 0.30 (expressers) mg/kg/d. The authors evaluated the occurrence of overexposures (12 < C 0 < 20 ng/mL) or toxic concentrations (C 0 ≥ 20 ng/mL). These results were used to set up a new strategy based on the 3 distinct CYP3A5 genotypes, which relevance was evaluated in a prospective cohort of 107 patients. RESULTS In the retrospective cohort, non-expressers exhibited frequent overexposure (63.6%) or toxic C 0 (20.8%). Among expressers, none of the homozygous *1 carriers exhibited overexposure contrary to 25% of the heterozygotes. Based on these results, new tacrolimus starting doses were set at 0.10, 0.20, and 0.30 mg/kg/d for CYP3A5*3/*3, CYP3A5*1/*3, and CYP3A5*1/*1 genotypes, respectively. Tacrolimus overexposure was reduced in the CYP3A5*3/*3 group (63.6% vs 40%, P = .0038). None of the heterozygous patients exhibited toxic tacrolimus C 0. Clinical outcomes were not different between the 2 periods, whatever the genotype. Our results indicate that the best tacrolimus exposure was obtained for doses of 0.10, 0.20, and 0.20 mg/kg/d for CYP3A5*3/3, CYP3A5*1/*3, and CYP3A5*1/*1, respectively. CONCLUSIONS Our results confirm that selecting tacrolimus dosing regimen according to the expected phenotype is appropriate, but that lower than currently recommended doses may be preferable.
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Affiliation(s)
- Bérenger Largeau
- CHRU de Tours, Laboratoire de Biochimie et Biologie Moléculaire, Tours, France
| | - Chantal Barin-Le Guellec
- Université de Tours, Université de Limoges, INSERM, Individual profiling and prevention of risks with immunosuppressive therapies and transplantation (IPPRITT) - UMR 1248, CHRU de Tours, Laboratoire de Biochimie et Biologie Moléculaire, Tours, France
| | - Hélène Longuet
- CHRU de Tours, Service de Néphrologie-Hypertension artérielle, Dialyses et Transplantation Rénale, FHU SUPORT, Tours, France
| | - Philippe Lesne
- CHRU de Tours, Laboratoire de Biochimie et Biologie Moléculaire, Tours, France
| | - Antoine Bouvarel
- CHRU de Tours, Laboratoire de Biochimie et Biologie Moléculaire, Tours, France
| | - Laura Préteseille
- CHRU de Tours, Laboratoire de Biochimie et Biologie Moléculaire, Tours, France
| | - Pierre Marquet
- Université de Limoges, INSERM, Individual profiling and prevention of risks with immunosuppressive therapies and transplantation (IPPRITT) - UMR 1248, CHU de Limoges, Service de Pharmacologie et Toxicologie, FHU SUPORT, Limoges, France
| | - Jean-Michel Halimi
- Université de Tours, Transplantation, immunologie et inflammation (T2I) - EA4245, CHRU de Tours, Service de Néphrologie-Hypertension artérielle, Dialyses et Transplantation Rénale, FHU SUPORT, Tours, France
| | - Matthias Büchler
- Université de Tours, Transplantation, immunologie et inflammation (T2I) - EA4245, CHRU de Tours, Service de Néphrologie-Hypertension artérielle, Dialyses et Transplantation Rénale, FHU SUPORT, Tours, France
| | - Philippe Gatault
- Université de Tours, Transplantation, immunologie et inflammation (T2I) - EA4245, CHRU de Tours, Service de Néphrologie-Hypertension artérielle, Dialyses et Transplantation Rénale, FHU SUPORT, Tours, France
| | - Johan Noble
- CHRU de Tours, Service de Néphrologie-Hypertension artérielle, Dialyses et Transplantation Rénale, FHU SUPORT, Tours, France
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29
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Clayton PA, McDonald SP, Russ GR, Chadban SJ. Long-Term Outcomes after Acute Rejection in Kidney Transplant Recipients: An ANZDATA Analysis. J Am Soc Nephrol 2019; 30:1697-1707. [PMID: 31308074 DOI: 10.1681/asn.2018111101] [Citation(s) in RCA: 95] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Accepted: 05/20/2019] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Declining rates of acute rejection (AR) and the high rate of 1-year graft survival among patients with AR have prompted re-examination of AR as an outcome in the clinic and in trials. Yet AR and its treatment may directly or indirectly affect longer-term outcomes for kidney transplant recipients. METHODS To understand the long-term effect of AR on outcomes, we analyzed data from the Australia and New Zealand Dialysis and Transplant Registry, including 13,614 recipients of a primary kidney-only transplant between 1997 and 2017 with at least 6 months of graft function. The associations between AR within 6 months post-transplant and subsequent cause-specific graft loss and death were determined using Cox models adjusted for baseline donor, recipient, and transplant characteristics. RESULTS AR occurred in 2906 recipients (21.4%) and was associated with graft loss attributed to chronic allograft nephropathy (hazard ratio [HR], 1.39; 95% confidence interval [95% CI], 1.23 to 1.56) and recurrent AR beyond month 6 (HR, 1.85; 95% CI, 1.39 to 2.46). Early AR was also associated with death with a functioning graft (HR, 1.22; 95% CI, 1.08 to 1.36), and with death due to cardiovascular disease (HR, 1.30; 95% CI, 1.11 to 1.53) and cancer (HR, 1.35; 95% CI, 1.12 to 1.64). Sensitivity analyses restricted to subgroups with either biopsy-proven, antibody-mediated, or vascular rejection, or stratified by treatment response produced similar results. CONCLUSIONS AR is associated with increased risks of longer-term graft failure and death, particularly death from cardiovascular disease and cancer. The results suggest AR remains an important short-term outcome to monitor in kidney transplantation and clinical trials.
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Affiliation(s)
- Philip A Clayton
- Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, Australia.,Adelaide Medical School, University of Adelaide, Adelaide, Australia.,Central and Northern Adelaide Renal and Transplantation Service, Royal Adelaide Hospital, Adelaide, Australia
| | - Stephen P McDonald
- Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, Australia.,Adelaide Medical School, University of Adelaide, Adelaide, Australia.,Central and Northern Adelaide Renal and Transplantation Service, Royal Adelaide Hospital, Adelaide, Australia
| | - Graeme R Russ
- Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, Australia.,Adelaide Medical School, University of Adelaide, Adelaide, Australia.,Central and Northern Adelaide Renal and Transplantation Service, Royal Adelaide Hospital, Adelaide, Australia
| | - Steven J Chadban
- Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, Australia; .,Department of Renal Medicine, Royal Prince Alfred Hospital, Sydney, Australia; and.,Kidney Node, Charles Perkins Centre, University of Sydney, Australia
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Therapeutic Drug Monitoring of Tacrolimus-Personalized Therapy: Second Consensus Report. Ther Drug Monit 2019; 41:261-307. [DOI: 10.1097/ftd.0000000000000640] [Citation(s) in RCA: 227] [Impact Index Per Article: 37.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Brunet M, van Gelder T, Åsberg A, Haufroid V, Hesselink DA, Langman L, Lemaitre F, Marquet P, Seger C, Shipkova M, Vinks A, Wallemacq P, Wieland E, Woillard JB, Barten MJ, Budde K, Colom H, Dieterlen MT, Elens L, Johnson-Davis KL, Kunicki PK, MacPhee I, Masuda S, Mathew BS, Millán O, Mizuno T, Moes DJAR, Monchaud C, Noceti O, Pawinski T, Picard N, van Schaik R, Sommerer C, Vethe NT, de Winter B, Christians U, Bergan S. Therapeutic Drug Monitoring of Tacrolimus-Personalized Therapy: Second Consensus Report. Ther Drug Monit 2019. [DOI: 10.1097/ftd.0000000000000640
expr 845143713 + 809233716] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2023]
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Jouve T, Noble J, Rostaing L, Malvezzi P. An update on the safety of tacrolimus in kidney transplant recipients, with a focus on tacrolimus minimization. Expert Opin Drug Saf 2019; 18:285-294. [DOI: 10.1080/14740338.2019.1599858] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Thomas Jouve
- Service de Néphrologie, Hémodialyse, Aphérèses et Transplantation Rénale, CHU Grenoble-Alpes, Grenoble, France
- Université Grenoble Alpes, Grenoble, France
| | - Johan Noble
- Service de Néphrologie, Hémodialyse, Aphérèses et Transplantation Rénale, CHU Grenoble-Alpes, Grenoble, France
- Université Grenoble Alpes, Grenoble, France
| | - Lionel Rostaing
- Service de Néphrologie, Hémodialyse, Aphérèses et Transplantation Rénale, CHU Grenoble-Alpes, Grenoble, France
- Université Grenoble Alpes, Grenoble, France
| | - Paolo Malvezzi
- Service de Néphrologie, Hémodialyse, Aphérèses et Transplantation Rénale, CHU Grenoble-Alpes, Grenoble, France
- Université Grenoble Alpes, Grenoble, France
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Tacrolimus Variability: A Cause of Donor-Specific Anti-HLA Antibody Formation in Children. Eur J Drug Metab Pharmacokinet 2019; 44:539-548. [DOI: 10.1007/s13318-019-00544-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Accepted: 01/23/2019] [Indexed: 10/27/2022]
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