Abstract
Purpose
Immunosuppressive therapy plays a major role in the development of post-transplant cancer. In this nested case–control study of kidney transplant recipients (KTRs), we investigated whether the incidence of post-transplant cancer is associated with the level of tacrolimus exposure over time.
Methods
We screened the Rabin Medical Center database for adults who received kidney transplants between 2001 and 2014 and developed post-transplant cancer (excluding basal and squamous cell skin cancers). They were matched against KTRs without cancer. All patients received a maintenance immunosuppressive treatment with tacrolimus, mycophenolate mofetil and corticosteroids. The degree of exposure to tacrolimus was estimated as the time-weighted average (tTWA) value of tacrolimus blood levels. The tTWA was calculated as the area under the curve divided by time at 1, 6, and 12 months after transplantation and at time of cancer diagnosis.
Results
Thirty-two cases were matched against 64 controls. tTWA values above 11 ng/mL at 6 and 12 months after transplantation were associated with odds ratio (OR) of 3.1 (95% CI 1.1–9) and 11.7 (95% CI = 1.3–106), respectively, for post-transplant cancer; and with OR of 5.2 (95% CI 1.3–20.5) and 14.1 (95% CI = 1.5–134.3), respectively, for cancer diagnosed more than 3 years after transplantation.
Conclusion
Exposure to a tacrolimus time-weighted average level above 11 ng/mL at 6 or 12 months after kidney transplantation is associated with an increased risk of developing cancer.
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Acknowledgements
We wish to thank Ruth Miller for her linguistic assistance.
Authors’ Contribution Statement
Shelly Lichtenberg—research design, performance of research, data analysis, writing of manuscript
Ruth Rahamimov—research design, performance of research, data analysis, writing of manuscript
Hefziba Green—data analysis
Benjamin D Fox—performance of research, contribution of new models, data analysis
Eytan Mor—performance of research, data analysis
Uzi Gafter—data analysis
Avry Chagnac—data analysis, contribution of new models
Benaya Rozen-Zvi—research design, performance of research, data analysis, contribution of new methods and models, writing of manuscript
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The study was approved by the Rabin Medical Center Institutional Review Board (no. 0681-13-RMC) and conducted according to the declaration of Helsinki and the declaration of Istanbul.
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Shelly Lichtenberg and Ruth Rahamimov contributed equally to this work.
Electronic supplementary material
Supplementary figure 1
tTWA blood levels at 6 and 12 months in the whole population (early and late periods).
Boxplot showing the distribution of tTWA values at 6 months (n = 94) and 12 months (n = 82), with whiskers extending from minimum to maximum values. The dotted lines represent the limit above which data are considered outliers (= 75 percentile +1.5 x the interquartile range). Three (3.2%) and 4 (4.9%) of the values at 6 and 12 months, respectively, were outliers. (GIF 77 kb)
Supplementary figures 2 and 3
tTWA blood levels at 6 and 12 months in the non-cancer and cancer groups (late period - cancers diagnosed more than 3 years after transplantation).
Boxplots showing the distribution of tTWA levels (n = 46) at 6 months (Supplementary Fig. 2) and 12 months (Supplementary Fig. 3), with whiskers extending from minimum to maximum values. The dotted lines represent the limit above which the whole population data are considered outliers (Supplementary Fig. 1). High values were defined as the point data above this limit (13.3 ng/ml at 6 months, 11.8 ng/ml at 12 months). The data distribution of the cancer and that of the non-cancer groups differ, with high tTWA blood levels at 6 and 12 months being more prevalent in the cancer group than in the non-cancer group (3 of 15 patients versus 0 of 31 patients had high tTWA levels, respectively). (GIF 81 kb)
Supplementary figure 4
A receiver operating characteristic (ROC) curve illustrating the risk of post transplant cancer according to tTWA levels at 6 months after transplantation. (GIF 72 kb)
Supplementary figure 5
Odds ratio for cancer - tTWA ≤ 11 ng/mL versus tTWA > 11 ng/mL at 6 months after transplantation, adjusted and unadjusted for smoking. (GIF 53 kb)
Supplementary figure 6
Odds ratio for cancer - tTWA ≤ 11 ng/mL versus tTWA > 11 ng/mL at 12 months after transplantation, adjusted and unadjusted for smoking. (GIF 52 kb)
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Lichtenberg, S., Rahamimov, R., Green, H. et al. The incidence of post-transplant cancer among kidney transplant recipients is associated with the level of tacrolimus exposure during the first year after transplantation. Eur J Clin Pharmacol 73, 819–826 (2017). https://doi.org/10.1007/s00228-017-2234-2
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DOI: https://doi.org/10.1007/s00228-017-2234-2