Erratic tacrolimus exposure, assessed using the standard deviation of trough blood levels, predicts chronic lung allograft dysfunction and survival
Abstract
Background Erratic tacrolimus blood levels are associated with liver and kidney graft failure. We hypothesized that erratic tacrolimus exposure would similarly compromise lung transplant outcomes. This study assessed the effect of tacrolimus mean and standard deviation (SD) levels on the risk of chronic lung allograft dysfunction (CLAD) and death after lung transplantation. Methods We retrospectively reviewed 110 lung transplant recipients who received tacrolimus-based immunosuppression. Cox proportional hazard modeling was used to investigate the effect of tacrolimus mean and SD levels on survival and CLAD. At census, 48 patients (44%) had developed CLAD and 37 (34%) had died. Results Tacrolimus SD was highest for the first 6 post-transplant months (median, 4.01; interquartile range [IQR], 3.04-4.98 months) before stabilizing at 2.84 μg/liter (IQR, 2.16-4.13 μg/liter) between 6 and 12 months. The SD then remained the same (median, 2.85; IQR, 2.00-3.77 μg/liter) between 12 and 24 months. A high mean tacrolimus level 6 to 12 months post-transplant independently reduced the risk of CLAD (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.63-0.86; p < 0.001) but not death (HR, 0.96; 95% CI, 0.83-1.12; p = 0.65). In contrast, a high tacrolimus SD between 6 and 12 months independently increased the risk of CLAD (HR, 1.46; 95% CI, 1.23-1.73; p < 0.001) and death (HR, 1.27; 95% CI, 1.08-1.51; p = 0.005). Conclusions Erratic tacrolimus levels are a risk factor for poor lung transplant outcomes. Identifying and modifying factors that contribute to this variability may significantly improve outcomes.
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Higher mean tacrolimus trough levels 6-12 months after LTx were associated with reduced risk of CLAD, and higher standard deviations of tacrolimus levels correlated with the incidence of CLAD and death.
“Gallagher et al.[39] could demonstrate that higher mean tacrolimus trough levels 6–12 months after LTx were associated with reduced risk of CLAD but also that higher standard deviations of tacrolimus levels correlated with the incidence of CLAD and death.”
From Adherence is associated with a favorable outcome after lung transplantation (2019) · cites this paper as Gallagher et al.[39]
High variability of immunosuppressant blood levels was associated with unfavorable allograft outcome in solid organ transplant recipients, including patients after lung transplantation.
“High variability was associated with unfavorable allograft outcome in solid organ transplant recipients, including patients after lung transplantation[10,37–39].”
From Adherence is associated with a favorable outcome after lung transplantation (2019) · cites this paper as [39]
Cites
A Randomized Controlled Trial of Tacrolimus Versus Cyclosporine After Lung Transplantation
Hachem, R. R., Yusen, R. D., Chakinala, M. M., Meyers, B. F., Lynch, J. P., Aloush, A. A., Patterson, G. A., & Trulock, E. P. (2007) · The Journal of Heart and Lung Transplantation · doi:10.1016/j.healun.2007.07.027 · Cited by 160 · see citing works
Treede, H., Glanville, A. R., Klepetko, W., Aboyoun, C., Vettorazzi, E., Lama, R., Bravo, C., Knoop, C., Aubert, J.-D., & Reichenspurner, H. (2012) · The Journal of Heart and Lung Transplantation · doi:10.1016/j.healun.2012.03.008 · Cited by 130 · see citing works
Treede, H., Klepetko, W., Reichenspurner, H., Zuckermann, A., Meiser, B., Birsan, T., Wisser, W., & Reichert, B. (2001) · The Journal of Heart and Lung Transplantation · doi:10.1016/s1053-2498(01)00244-3 · Cited by 108 · see citing works
Adherence to immunosuppression in adult lung transplant recipients: Prevalence and risk factors
Bosma, O. H., Vermeulen, K. M., Verschuuren, E. A., Erasmus, M. E., & van der Bij, W. (2011) · The Journal of Heart and Lung Transplantation · doi:10.1016/j.healun.2011.05.007 · Cited by 40 · see citing works
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Andrews, L. M., Li, Y., De Winter, B. C. M., Shi, Y.-Y., Baan, C. C., Van Gelder, T., & Hesselink, D. A. (2017) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1080/17425255.2017.1395413 · Cited by 142 · see citing works
Adherence is associated with a favorable outcome after lung transplantation
Bertram, A., Fuge, J., Suhling, H., Tudorache, I., Haverich, A., Welte, T., & Gottlieb, J. (2019) · PLoS ONE · doi:10.1371/journal.pone.0226167 · Cited by 34 · see citing works
“Gallagher et al.[39] could demonstrate that higher mean tacrolimus trough levels 6–12 months after LTx were associated with reduced risk of CLAD but also that higher standard deviations of tacrolimus levels correlated with the incidence of CLAD and death.”
Background
- Authors
- Gallagher, H. M., Sarwar, G., Tse, T., Sladden, T. M., Hii, E., Yerkovich, S. T., Hopkins, P. M., & Chambers, D. C.
- Affiliations
- Waikato Hospital (NZ)
- Prince Charles Hospital (AU)
- The University of Queensland (AU)
- Corresponding author
- Chambers, Daniel C.
- Venue
- The Journal of Heart and Lung Transplantation
- Publisher
- Elsevier BV
- Published
- 2015-11
- Volume
- 34
- Issue
- 11
- Pages
- 1442-1448
- ISSN
- 1053-2498 (ISSN-L)
- OpenAlex
- W2130592313
- Cited by
- 51
- References
- 4
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 6 · 2023: 6 · 2022: 4 · 2021: 6 · 2020: 2 · 2019: 10 · 2018: 8 · 2017: 2 · 2016: 1
- FWCI
- 3.70
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Heart and Lung Transplantation (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Surgery › Transplantation: Methods and Outcomes
- Health Sciences › Medicine › Transplantation › Renal Transplantation Outcomes and Treatments
- Health Sciences › Medicine › Transplantation › Organ and Tissue Transplantation Research
- Keywords
- tacrolimus, drug exposure variability, chronic lung allograft dysfunction, lung transplantation, immunosuppression, graft survival, post-transplant mortality
- MeSH terms
- Adult, Chronic Disease, Dose-Response Relationship, Drug, Female, Follow-Up Studies, Graft Rejection, Graft Survival, Humans, Immunosuppression Therapy, Immunosuppressive Agents, Male, Middle Aged, New Zealand, Prognosis, Queensland, Retrospective Studies, Risk Factors, Survival Rate, Proportional Hazards Models, Lung Transplantation, Tacrolimus, Allografts
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