A comprehensive review of the impact of tacrolimus intrapatient variability on clinical outcomes in kidney transplantation

Gonzales, Haley; McGillicuddy, John W.; Rohan, Vinayak; Chandler, Jessica; Nadig, Satish N.; DuBay, Derek A.; Taber, David J.

doi:10.1111/ajt.16002

Cited by 61 publications

(109 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Based on the extent of literature evaluating CV, ease of calculation, and standardization for the scale of the dataset, we agree with previous recommendations that CV is the best supported IPV metric for clinical use 5,6 . Considering CV within a highly adherent population approximated 15%; CV greater than 15% indicates a potential risk for poor outcomes.…”

Section: Discussionsupporting

confidence: 82%

“…After this time period, IPV likely better reflects patient behaviors and clinical conditions of interest. Others have recommended measuring IPV between 6 and 12 months posttransplant due to the limited data outside this time period 5,6 . Prior to this period, achieving therapeutic tacrolimus troughs should be the focus to optimize outcomes.…”

Section: Discussionmentioning

confidence: 99%

“…We recommend no less than three levels when calculating IPV and ideally at least one level per month, to best replicate available literature. Additionally, we recommend the use of only outpatient levels due to the added variability anticipated within the inpatient setting 5,6 . We also urge clinicians to be cautious when calculating and interpreting IPV.…”

Section: Discussionmentioning

confidence: 99%

“…In recent years, intrapatient variability (IPV) in trough concentrations has become recognized as a novel marker to identify transplant recipients at risk for poor outcomes, such as rejection and graft loss 4–6 . IPV describes the extent of variation in tacrolimus trough concentrations over time for a single patient and is frequently expressed using standard deviation (SD), coefficient of variation (CV), and time in therapeutic range (TTR).…”

Section: Introductionmentioning

confidence: 99%

“…Previous published reviews on tacrolimus IPV provided a focused examination of available literature, with conclusions generally derived from data in adult kidney transplant recipients 4–6 . In this systematic review, we critically evaluate the literature for the relationship between tacrolimus IPV and outcomes in solid organ transplantation, and discuss the strategies that have been utilized to reduce IPV.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Tacrolimus intrapatient variability in solid organ transplantation: A multiorgan perspective

2020

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Tacrolimus intrapatient variability in solid organ transplantation: A multiorgan perspective

2020

View full text Add to dashboard Cite

show abstract

Tacrolimus Pharmacokinetics is Associated with Gut Microbiota Diversity in Kidney Transplant Patients: Results from a Pilot Cross‐Sectional Study

Degraeve,

Bindels,

Haufroid

et al. 2023

Clin Pharma and Therapeutics

View full text Add to dashboard Cite

Clinical use of tacrolimus, an essential immunosuppressant following transplantation, is complexified by its high pharmacokinetic variability. The gut microbiota gains growing interest but limited investigations have evaluated its contribution to tacrolimus pharmacokinetics. Here, we explore the associations between the gut microbiota composition and tacrolimus pharmacokinetics. In this pilot cross‐sectional study (Clinicaltrial.gov NCT04360031), we recruited 93 CYP3A5 non‐expressers stabilized kidney transplant patients. Gut microbiota composition was characterized by 16S rRNA gene sequencing, tacrolimus pharmacokinetic parameters were computed, and additional demographical and medical covariates were collected. Associations between pharmacokinetic parameters or diabetic status and the gut microbiota composition, as reflected by α‐ and β‐diversity metrics, were evaluated. Patients with higher tacrolimus AUC/(dose/kg) had higher bacterial richness, and tacrolimus pharmacokinetic parameters were associated with specific bacterial taxa (e.g., Bilophila) and amplicon sequence variant (ASV) (e.g., ASV 1508 and ASV 1982 [Veillonella/unclassified Sporomusaceae]; ASV 664 [unclassified Oscillospiraceae]). Building a multiple linear regression model showed that ASV 1508 (co‐abundant with ASV 1982) and ASV 664 explained respectively 16.0% and 4.6% of the inter‐individual variability in tacrolimus AUC/(dose/kg) in CYP3A5 non‐expressers patients, when adjusting for haematocrit and age. Anaerostipes relative abundance was decreased in diabetic patients. Altogether, this pilot study revealed unprecedented links between the gut microbiota composition and diversity and tacrolimus pharmacokinetics in stable kidney transplant patients. It supports the relevance of studying the gut microbiota as an important contributor to tacrolimus pharmacokinetic variability. Elucidating the causal relationship will offer new perspectives to predict tacrolimus inter‐ and intra‐pharmacokinetic variability.

show abstract

Deep phenotyping of T cell populations under long‐term treatment of tacrolimus and rapamycin in patients receiving renal transplantations by mass cytometry

Shen

Wang

et al. 2021

Clinical & Translational Med

View full text Add to dashboard Cite

Tacrolimus (FK506) and rapamycin (RAPA) are widely used to maintain long‐term immunosuppression after organ transplantation. However, the impact of accumulative drug administration on the recipients’ immune systems remains unclear. We investigated the impact of 3‐year FK506 or RAPA treatment after renal transplantation on the human immune systems. A discovery cohort of 30 patients was first recruited, and we discovered two distinctive T lineage suppressive regulatory patterns induced by chronic treatment of FK506 and RAPA. The increased percentage of senescent CD8+CD57+ T lineages and less responsive T cell receptor (TCR) pathway in the FK506 group indicate better graft acceptance. Meanwhile, percentages of regulatory T cells (Tregs) and expression of CTLA‐4 were both up to two‐fold higher in the RAPA group, suggesting the inconsistent reactivation potential of the FK506 and RAPA groups when an anti‐tumour or anti‐infection immune response is concerned. Additionally, up‐regulation of phosphorylated signaling proteins in T lineages after in vitro CD3/CD28 stimulation suggested more sensitive TCR‐signaling pathways reserved in the RAPA group. An independent validation cohort of 100 renal transplantation patients was further investigated for the hypothesis that long‐term RAPA administration mitigates the development of tumours and infections during long‐term intake of immunosuppressants. Our results indicate that RAPA administration indeed results in less clinical oncogenesis and infection. The deep phenotyping of T‐cell lineages, as educated by the long‐term treatment of different immunosuppressants, provides new evidence for personalized precision medicine after renal transplantations.

show abstract

A comprehensive review of the impact of tacrolimus intrapatient variability on clinical outcomes in kidney transplantation

Abstract: Rohan V, et al. A comprehensive review of the impact of tacrolimus intrapatient variability on clinical outcomes in kidney transplantation.

Cited by 61 publications

References 23 publications

Tacrolimus intrapatient variability in solid organ transplantation: A multiorgan perspective

Tacrolimus intrapatient variability in solid organ transplantation: A multiorgan perspective

Tacrolimus Pharmacokinetics is Associated with Gut Microbiota Diversity in Kidney Transplant Patients: Results from a Pilot Cross‐Sectional Study

Deep phenotyping of T cell populations under long‐term treatment of tacrolimus and rapamycin in patients receiving renal transplantations by mass cytometry

Contact Info

Product

Resources

About