Vol. 152 No. 2930 (2022)
Influence of mycophenolate mofetil dosage and plasma levels on the occurrence of chronic lung allograft dysfunction in lung transplants: a retrospective cohort analysis
- Carolin Steinack
- Philipp Saurer
- Fiorenza Gautschi
- René Hage
- Gernot Ortmanns
- Macé M. Schuurmans
- Thomas Gaisl
INTRODUCTION: Development of chronic lung allograft dysfunction is a limiting factor for post-lung transplant survival. We evaluated whether the dose of the immunosuppressant mycophenolate mofetil or plasma concentrations of the active metabolite mycophenolic acid affect the development of chronic lung allograft dysfunction.
METHODS: In this retrospective cohort study we recruited 71 patients with a lung transplant between 2010 and 2014 which survived the first year after transplantation up to 1 July 2021. An event-time-analytical Cox proportional-hazards regression model with time-varying-covariates (18,431 measurements for MPA, mycophenolate mofetil dosage, lymphocytes) was used to predict chronic lung allograft dysfunction, with adjustment for sociodemographic factors and lung function at baseline.
RESULTS: 37 patients did not develop chronic lung allograft dysfunction (age 41.3 ± 15.6 years, baseline FEV1 95.5 ± 19.1% predicted) and 34 patients developed chronic lung allograft dysfunction (age 50.9 ± 13.3 years, baseline FEV1 102.2 ± 25.4% predicted). Mean mycophenolic acid did not differ significantly between the groups (2.8 ± 1.7 and 3.0 ± 2.3 mg/l; p = 0.724). In the first 4 post-transplant years the death rate was 25%. A total of 50% of the patients died by the ninth post-transplant year. There was a dose-effect relationship between mycophenolate mofetil dosage, mycophenolic acid (r2 = 0.02, p <0.001), as well as lymphocyte levels (r2 = –0.007, p <0.001), but only the traditional risk factor age predicted chronic lung allograft dysfunction. Continuously measured mycophenolic acid did not predict chronic lung allograft dysfunction (hazard ratio 0.98, 95% confidence interval 0.90–1.06, p = 0.64 over a period of 382.97 patient-years).
CONCLUSION: Mycophenolate mofetil dosage and mycophenolic acid were not associated with chronic lung allograft dysfunction development. Thus, the mycophenolate mofetil dose or mycophenolic acid plasma concentration are not a primary factor related to organ rejection, but chronic lung allograft dysfunction may be influenced by other components of immunosuppression or other factors.
- Scheffert JL, Raza K. Immunosuppression in lung transplantation. J Thorac Dis. 2014 Aug;6(8):1039–53.
- Verleden GM, Glanville AR, Lease ED, Fisher AJ, Calabrese F, Corris PA, et al. Chronic lung allograft dysfunction: Definition, diagnostic criteria, and approaches to treatment-A consensus report from the Pulmonary Council of the ISHLT. J Heart Lung Transplant. 2019 May;38(5):493–503. https://doi.org/10.1016/j.healun.2019.03.009
- Society I. Transplantation oHaL. Overall Lung Transplantation Statistics 2019 Slides [Available from: https://ishltregistries.org/registries/slides.asp
- Erasmus ME, van der Bij W. Death after lung transplantation: improving long term survival despite perilous early postoperative years. Transpl Int. 2020 Feb;33(2):128–9. https://doi.org/10.1111/tri.13553
- Chambers DC, Zuckermann A, Cherikh WS, Harhay MO, Hayes D Jr, Hsich E, et al.; International Society for Heart and Lung Transplantation. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: 37th adult lung transplantation report - 2020; focus on deceased donor characteristics. J Heart Lung Transplant. 2020 Oct;39(10):1016–27. https://doi.org/10.1016/j.healun.2020.07.009
- Bos S, Vos R, Van Raemdonck DE, Verleden GM. Survival in adult lung transplantation: where are we in 2020? Curr Opin Organ Transplant. 2020 Jun;25(3):268–73. https://doi.org/10.1097/MOT.0000000000000753
- Chambers DC, Cherikh WS, Harhay MO, Hayes D Jr, Hsich E, Khush KK, et al.; International Society for Heart and Lung Transplantation. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Thirty-sixth adult lung and heart-lung transplantation Report-2019; Focus theme: Donor and recipient size match. J Heart Lung Transplant. 2019 Oct;38(10):1042–55. https://doi.org/10.1016/j.healun.2019.08.001
- Meyer KC. Recent advances in lung transplantation. F1000 Res. 2018 Oct;7:7. https://doi.org/10.12688/f1000research.15393.1
- Greer M, Werlein C, Jonigk D. Surveillance for acute cellular rejection after lung transplantation. Ann Transl Med. 2020 Mar;8(6):410. https://doi.org/10.21037/atm.2020.02.127
- Koutsokera A. Rethinking bronchoalveolar lavage in acute cellular rejection: how golden is the standard of transbronchial biopsies? J Heart Lung Transplant. 2019 Aug;38(8):856–7. https://doi.org/10.1016/j.healun.2019.06.016
- Weigt SS, Wang X, Palchevskiy V, Li X, Patel N, Ross DJ, et al. Usefulness of gene expression profiling of bronchoalveolar lavage cells in acute lung allograft rejection. J Heart Lung Transplant. 2019 Aug;38(8):845–55. https://doi.org/10.1016/j.healun.2019.05.001
- Speich R, Schneider S, Hofer M, Irani S, Vogt P, Weder W, et al. Mycophenolate mofetil reduces alveolar inflammation, acute rejection and graft loss due to bronchiolitis obliterans syndrome after lung transplantation. Pulm Pharmacol Ther. 2010 Oct;23(5):445–9. https://doi.org/10.1016/j.pupt.2010.04.004
- Knight SR, Russell NK, Barcena L, Morris PJ. Mycophenolate mofetil decreases acute rejection and may improve graft survival in renal transplant recipients when compared with azathioprine: a systematic review. Transplantation. 2009 Mar;87(6):785–94. https://doi.org/10.1097/TP.0b013e3181952623
- Ting LS, Partovi N, Levy RD, Riggs KW, Ensom MH. Limited sampling strategy for predicting area under the concentration-time curve of mycophenolic acid in adult lung transplant recipients. Pharmacotherapy. 2006 Sep;26(9):1232–40. https://doi.org/10.1592/phco.26.9.1232
- Minagawa K, Yamamori M, Katayama Y, Matsui T. Mycophenolate mofetil: fully utilizing its benefits for GvHD prophylaxis. Int J Hematol. 2012 Jul;96(1):10–25. https://doi.org/10.1007/s12185-012-1086-x
- Knight SR, Morris PJ. Does the evidence support the use of mycophenolate mofetil therapeutic drug monitoring in clinical practice? A systematic review. Transplantation. 85. United States2008. p. 1675-85.
- Tague LK, Byers DE, Hachem R, Kreisel D, Krupnick AS, Kulkarni HS, et al. Impact of SLCO1B3 polymorphisms on clinical outcomes in lung allograft recipients receiving mycophenolic acid. Pharmacogenomics J. 2020 Feb;20(1):69–79. https://doi.org/10.1038/s41397-019-0086-0
- Pillans PI, Rigby RJ, Kubler P, Willis C, Salm P, Tett SE, et al. A retrospective analysis of mycophenolic acid and cyclosporin concentrations with acute rejection in renal transplant recipients. Clin Biochem. 2001 Feb;34(1):77–81. https://doi.org/10.1016/S0009-9120(00)00196-X
- Wollenberg K, Krumme B, Schollmeyer P, Kirste G. Pharmacokinetics of mycophenolic acid after renal transplantation. Transplant Proc. 1998 Aug;30(5):2237–9. https://doi.org/10.1016/S0041-1345(98)00604-6
- Schuurmans MM, Tini GM, Zuercher A, Hofer M, Benden C, Boehler A. Practical approach to emergencies in lung transplant recipients: how we do it. Respiration. 2012;84(2):163–75. https://doi.org/10.1159/000339345
- Schuurmans MM, Benden C, Inci I. Practical approach to early postoperative management of lung transplant recipients. Swiss Med Wkly. 2013 Apr;143:w13773. https://doi.org/10.4414/smw.2013.13773
- Fisher LD, Lin DY. Time-dependent covariates in the Cox proportional-hazards regression model. Annu Rev Public Health. 1999;20(1):145–57. https://doi.org/10.1146/annurev.publhealth.20.1.145
- Hofer M, Benden C, Inci I, Schmid C, Irani S, Speich R, et al. True survival benefit of lung transplantation for cystic fibrosis patients: the Zurich experience. J Heart Lung Transplant. 2009 Apr;28(4):334–9. https://doi.org/10.1016/j.healun.2008.12.025
- Le Meur Y, Büchler M, Thierry A, Caillard S, Villemain F, Lavaud S, et al. Individualized mycophenolate mofetil dosing based on drug exposure significantly improves patient outcomes after renal transplantation. Am J Transplant. 2007 Nov;7(11):2496–503. https://doi.org/10.1111/j.1600-6143.2007.01983.x
- Yabuki H, Matsuda Y, Watanabe T, Eba S, Hoshi F, Hirama T, et al. Plasma mycophenolic acid concentration and the clinical outcome after lung transplantation. Clin Transplant. 2020 Dec;34(12):e14088. https://doi.org/10.1111/ctr.14088
- Tanaka M, Kikuchi M, Takasaki S, Hirasawa T, Sigeta K, Noda A, et al. Limited Sampling Strategy for the Estimation of Mycophenolic Acid and its Acyl Glucuronide Metabolite Area under the Concentration-Time Curve in Japanese Lung Transplant Recipients. J Pharm Pharm Sci. 2019;22(1):407–17. https://doi.org/10.18433/jpps30505
- Gallagher HM, Sarwar G, Tse T, Sladden TM, Hii E, Yerkovich ST, et al. Erratic tacrolimus exposure, assessed using the standard deviation of trough blood levels, predicts chronic lung allograft dysfunction and survival. J Heart Lung Transplant. 2015 Nov;34(11):1442–8. https://doi.org/10.1016/j.healun.2015.05.028